Compounds and methods for treating diabetes

ABSTRACT

Hydrogenated pyrido[4,3-b]indoles, pyrido[3,4-b]indoles and azepino[4,5-b]indoles are described. The compounds may bind to and are antagonists of the adrenergic receptor α 2A . The compounds may also bind to and are an antagonist of the adrenergic receptor α 2B ; or the compounds are not antagonists of the adrenergic receptor α 2B  and the compounds are administered in conjunction with a second agent that reduces, or is expected to reduce, blood pressure in an individual. The compounds may find use in therapy, e.g., to regulate blood glucose level, increase insulin secretion and treat diseases or conditions that are, or are expected to be, responsive to an increase in insulin production. Use of the compounds to treat type 2 diabetes is particularly described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/400,032, filed Feb. 17, 2012, which claims priority to U.S.Provisional Patent Application No. 61/444,642 filed Feb. 18, 2011, U.S.Provisional Patent Application No. 61/444,655 filed Feb. 18, 2011, U.S.Provisional Patent Application No. 61/444,659 filed Feb. 18, 2011, U.S.Provisional Patent Application No. 61/469,664 filed Mar. 30, 2011, U.S.Provisional Patent Application No. 61/529,745 filed Aug. 31, 2011, U.S.Provisional Patent Application No. 61/529,816 filed Aug. 31, 2011, U.S.Provisional Patent Application No. 61/562,927 filed Nov. 22, 2011 andU.S. Provisional Patent Application No. 61/562,938 filed Nov. 22, 2011,the disclosures of each of which are incorporated herein by reference intheir entireties.

BACKGROUND OF THE INVENTION

Type 2 diabetes is a serious and prevalent disease. This form ofdiabetes may involve insulin resistance and impaired insulin release.Approximately 25.8 million people in the United States alone suffer fromdiabetes, whereby type 2 diabetes accounts for about 90-95% of alldiagnosed diabetes cases. From 1980 to 2008 the number of Americans withdiabetes has more than tripled. Diabetes is also increasingly prevalentelsewhere, such as in certain Asian countries whose populations haveexperienced a dramatic increase in the disease. For example, in Indiaand China, where rapid lifestyle and economic changes have led to a moresedentary lifestyle and poorer diet among the overall population,diabetes is becoming a major health concern. In addition, more than athird of adults at least 20 years old have pre-diabetes, which is asignificant risk factor for developing type 2 diabetes. Other diseasesand indications, such as glucose intolerance and metabolic syndrome mayalso be associated with impaired insulin release.

There remains a need for new and improved therapies that enhance insulinsecretion and/or promote insulin release into the blood stream inindividuals who have a reduced or impaired ability to secrete insulinand/or release insulin into the blood stream.

BRIEF SUMMARY OF THE INVENTION

Hydrogenated pyrido[4,3-b]indoles, pyrido[3,4-b]indoles andazepino[4,5-b]indoles are described. Compositions and kits comprisingthe compounds are also provided, as are methods of using and making thecompounds. Compounds provided herein may find use in therapy, e.g., toregulate blood glucose level, increase insulin secretion and treatdiseases or conditions that are, or are expected to be, responsive to anincrease in insulin production. In one aspect, compounds provided hereinare α_(2A) antagonists that may find use in therapy, e.g., to increaseinsulin secretion and treat diseases or conditions that are, or areexpected to be, responsive to an increase in insulin production. Use ofthe compounds to treat type 2 diabetes is particularly described.

In one aspect, the present invention discloses methods of regulatingblood glucose levels in an individual in need thereof comprisingadministering to the individual an effective amount of a compound of theformula (I):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H; C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, hydroxyl,carboxyl, SO₃H, SR^(1a), S(O)R^(1a), SO₂R^(1a) and perhaloalkyl; C₃-C₈cycloalkyl optionally substituted with 1 to 3 substituents independentlyselected from the group consisting of halo, hydroxyl, carboxyl andperhaloalkyl; C₂-C₅ alkenyl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,hydroxyl, carboxyl and perhaloalkyl; or —C(O)O—C₁-C₅ alkyl; or is takentogether with R^(2a) or R^(3a) to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(4a)or R^(5a), where present, to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety;

R^(1a) is H or optionally substituted C₁-C₅ alkyl;

R^(2a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR¹ or R^(5a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety ora butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(3a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;or is taken together with R^(4a), where present, to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(3a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR¹ or R^(4a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety ora butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(2a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;or is taken together with R^(5a), where present, to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(4a), where present, is H; halo; hydroxyl; cyano; carboxyl;—OC(O)N(R^(14a))R^(15a); —C(O)N(R^(14a))R^(15a); optionally substitutedC₁-C₅ alkyl; optionally substituted C₂-C₅ alkenyl; or optionallysubstituted aryl; or is taken together with R^(3a) to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; or is takentogether with R¹ to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety; or is taken together with R^(2a) to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety; or is takentogether with R^(5a), where present, to form a methylene (—CH₂—) moiety;

R^(5a), where present, is H; halo; hydroxyl; cyano; carboxyl;—OC(O)N(R^(14a))R^(15a); —C(O)N(R^(14a))R^(15a); optionally substitutedC₁-C₅ alkyl; optionally substituted C₂-C₅ alkenyl; or optionallysubstituted aryl; or is taken together with R^(2a) to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; or is takentogether with R¹ to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety; or is taken together with R^(3a) to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety; or is takentogether with R^(4a), where present, to form a methylene (—CH₂—) moiety;

each R^(2b) and R^(3b) is independently H, optionally substituted C₁-C₅alkyl, optionally substituted C₂-C₅ alkenyl, or optionally substitutedaryl;

each R^(4b) and R^(5b), where present, is independently H, halo,optionally substituted C₁-C₅ alkyl, optionally substituted C₂-C₅alkenyl, or optionally substituted aryl;

each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0;

each X¹, X², X and U is independently N or CR⁶;

each R⁶ is independently H; hydroxyl; halo; C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxyl, carboxyl and perhaloalkyl; C₂-C₅alkenyl; optionally substituted C₁-C₅ alkoxy; or optionally substituted—C(O)C₁-C₅ alkyl;

R⁷ is H; halo; optionally substituted C₁-C₅ alkyl; or optionallysubstituted aryl; or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;or is taken together with R⁹ to form a C₃-C₅ alkylene when R⁸ and R¹⁰are taken together to form a bond;

R⁸ is H; halo; hydroxyl; azido; aminoacyl, carboxyl; carbonylalkoxy;N(R¹¹)R¹²; SR¹³S(O)R¹³; SO₂R¹³; —OC(O)N(R¹⁴)R¹⁵; —C(O)N(R¹⁴)R¹⁵;optionally substituted —OC(O)-aryl; optionally substituted—OC(O)-heteroaryl; —OC(O)C₁-C₆ alkyl optionally substituted with aminoor carboxyl; or —OC₁-C₅ alkyl optionally substituted with carboxyl; oris taken together with R⁷ and the carbon atom to which they are attachedto form a dioxolane ring or a carbonyl moiety; or is taken together withR¹⁰ to form a bond;

R⁹ is H or optionally substituted C₁-C₅ alkyl, or is taken together withR⁷ to form a C₃-C₅ alkylene when R⁸ and R¹⁰ are taken together to form abond;

R¹⁰ is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R⁸ to form a bond;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene;

each R^(14a), and R^(15a) is independently H or optionally substitutedC₁-C₅ alkyl; and

Q is optionally substituted cycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl.

In one embodiment, the method reduces blood glucose level in theindividual. In another embodiment, the method reduces blood glucoselevel in the individual for a period of more than 0.5 hour followingadministration. In another embodiment, the method stabilizes bloodglucose level in the individual at a desired level.

In another aspect, the present invention provides methods of (i)increasing insulin secretion, and/or (ii) promoting insulin release intothe blood stream, in an individual in need thereof comprisingadministering to the individual an effective amount of a compound of theformula (I), or a salt, solvate or N-oxide thereof. In one embodiment,the method increases insulin secretion. In another embodiment, themethod promotes insulin release into the blood stream.

In one embodiment, the individual has a disease or condition thatinvolves impaired insulin secretion. In another embodiment, theindividual has one or more risk factors for developing a disease orcondition that involves impaired insulin secretion. In anotherembodiment, the administration results in decrease of blood pressure inthe individual.

In one aspect, a method is provided for one or more of the following:reducing blood glucose levels, increasing insulin secretion, andpromoting insulin release in the blood stream.

In another aspect, the invention presents methods of treating a diseaseor condition that is responsive to an increase in insulin secretion,comprising administering to an individual in need thereof an effectiveamount of a compound of the formula (I), or a salt, solvate or N-oxidethereof.

In a further aspect, the present invention provides methods of delayingthe onset of a disease or condition that is responsive to an increase ininsulin secretion, comprising administering to an individual in needthereof an effective amount of a compound of the formula (I), or a salt,solvate or N-oxide thereof.

In one embodiment, with respect to the method, the disease or conditionis type 2 diabetes. In another embodiment, the disease or condition isglucose intolerance. In another embodiment, the disease or condition ismetabolic syndrome.

In one embodiment, with respect to the above method, the individual isnot responsive to standard treatment of type 2 diabetes.

In another embodiment, with respect to the method, the method furthercomprising administering to the individual in need thereof one or moreanti-diabetic agents. In one embodiment, the anti-diabetic agents is aninsulin sensitizer.

In some embodiments, the compound used in the methods described above isa compound of formula (A-III):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H; C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, hydroxyl,carboxyl and perhaloalkyl; C₃-C₈ cycloalkyl optionally substituted with1 to 3 substituents independently selected from the group consisting ofhalo, hydroxyl, carboxyl and perhaloalkyl; C₂-C₅ alkenyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxyl, carboxyl and perhaloalkyl; or—C(O)O—C₁-C₅ alkyl; or is taken together with R^(2a) or R^(3a) to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; oris taken together with R^(4a) or R^(5a), where present, to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;

each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0;

R^(2a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR¹ or R^(5a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety ora butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(3a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;or is taken together with R^(4a), where present, to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(3a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR¹ or R^(4a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety ora butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(2a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;or is taken together with R^(5a), where present, to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(4a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR^(3a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R¹ to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety; or istaken together with R^(2a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety; or is taken together with R^(5a), wherepresent, to form a methylene (—CH₂—) moiety;

R^(5a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR^(2a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R¹ to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety; or istaken together with R^(3a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety; or is taken together with R^(4a), wherepresent, to form a methylene (—CH₂—) moiety;

each R^(2b), R^(3b), R^(4b) and R^(5b) is independently H, optionallysubstituted C₁-C₅ alkyl, optionally substituted C₂-C₅ alkenyl, oroptionally substituted aryl;

X is N or CR^(6a);

t is 1, 2 or 3;

each R⁶ and R^(6a) is independently H; hydroxyl; halo; C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl;C₂-C₅ alkenyl; optionally substituted C₁-C₅ alkoxy; or optionallysubstituted —C(O)C₁-C₅ alkyl;

R⁷ is H; halo; optionally substituted C₁-C₅ alkyl; or optionallysubstituted aryl; or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;or is taken together with R⁹ to form a C₃-C₅ alkylene when R⁸ and R¹⁰are taken together to form a bond;

R⁸ is H; halo; hydroxyl; N(R¹¹)R¹²; SR¹³, S(O)R¹³; SO₂R¹³;—OC(O)N(R¹⁴)R¹⁵; —OC(O)-aryl; —OC(O)-heteroaryl; or —OC(O)C₁-C₅ alkyloptionally substituted with amino; or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety; or is taken together with R¹⁰ to form a bond;

R⁹ is H or optionally substituted C₁-C₅ alkyl; or is taken together withR⁷ to form a C₃-C₈ alkylene when R⁸ and R¹⁰ are taken together to form abond;

R¹⁰ is H or optionally substituted C₁-C₅ alkyl; or is taken togetherwith R⁸ to form a bond;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl; or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

Q is unsubstituted aryl; unsubstituted heteroaryl; aryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino; or heteroaryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In some embodiments, the compound used in the methods described above isa compound of formula (A-III), wherein any one or more of provisions (1)to (34) apply:

(1) X is CR^(6a), wherein each R^(6a) is independently H, halo or C₁-C₅alkyl;

(2) each R⁶ is independently H, halo or C₁-C₅ alkyl;

(3) X is N;

(4) R¹ is H or C₁-C₅ alkyl;

(5) R^(2a) and R^(3a) is H;

(6) R⁷ is H or C₁-C₅ alkyl;

(8) R⁸ is H, hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl;

(9) R⁷ is H or C₁-C₅ alkyl, and R⁸ is H, hydroxyl, N(R¹¹)R¹² or—OC(O)C₁-C₅ alkyl;

(10) R⁷ is H, and R⁸ is H, hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl;

(11) R⁷ is C₁-C₅ alkyl, and R⁸ is H, hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅alkyl;

(12) R⁷ is H or C₁-C₅ alkyl, and R⁸ is H or hydroxyl;

(13) R⁷ is H or C₁-C₅ alkyl, and R⁸ is hydroxyl;

(14) R⁷ is H, and R⁸ is hydroxyl;

(15) R⁷ is methyl, and R⁸ is hydroxyl;

(16) R⁷ is H, and R⁸ is NH₂;

(17) R⁷ is H, and R⁸ is —OC(O)C₁-C₅ alkyl;

(18) R⁹ is H or C₁-C₅ alkyl;

(19) R¹⁰ is H or C₁-C₅ alkyl;

(20) each R⁹ and R¹⁰ is H;

(21) one of R⁹ and R¹⁰ is H and the other is C₁-C₅ alkyl;

(22) Q is: unsubstituted pyridyl; unsubstituted pyrimidyl; unsubstitutedpyrazinyl; unsubstituted phenyl; unsubstituted imidazolyl; unsubstitutedtriazolyl; pyridyl substituted with 1 to 3 substituents independentlyselected form the group consisting of halo, C₁-C₅ alkyl,halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷, wherein eachR¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅ alkyl;pyrimidyl substituted with 1 to 3 substituents independently selectedform the group consisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅alkyl, carboxyl and —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ isindependently H or optionally substituted C₁-C₅ alkyl; pyrazinylsubstituted with 1 to 3 substituents independently selected form thegroup consisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl,carboxyl and —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ is independently Hor optionally substituted C₁-C₅ alkyl; or phenyl substituted with 1 to 3substituents independently selected form the group consisting of halo,C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷,wherein each R¹⁶ and R¹⁷ is independently H or optionally substitutedC₁-C₅ alkyl; imidazolyl substituted with 1 to 3 substituentsindependently selected form the group consisting of halo, C₁-C₅ alkyl,halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷, wherein eachR¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅ alkyl; ortriazolyl substituted with 1 to 3 substituents independently selectedform the group consisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅alkyl, carboxyl and —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ isindependently H or optionally substituted C₁-C₅ alkyl;

(23) X is CR^(6a), wherein R^(6a) is H, halo or C₁-C₅ alkyl; and each R⁶is independently H, halo or C₁-C₅ alkyl;

(24) wherein R¹ is H or C₁-C₅ alkyl, R⁷ is H or C₁-C₅ alkyl, and R⁸ isH, hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl;

(25) wherein R¹ is H or C₁-C₅ alkyl, R⁷ is H or C₁-C₅ alkyl, and R⁸ is Hor hydroxyl;

(26) R¹ is H or C₁-C₅ alkyl, R⁷ is H or C₁-C₅ alkyl, and R⁸ is hydroxyl;

(27) wherein R¹ is CH₃, R⁷ is H, R⁸ is hydroxyl, n is zero and m is 1;

(28) R¹ is CH₃, R⁷ is methyl, R⁸ is hydroxyl, n is zero and m is 1;

(29) X is CR^(6a), wherein R^(6a) is H, halo or C₁-C₅ alkyl; each R⁶ isindependently H, halo or C₁-C₅ alkyl; R¹ is H or C₁-C₅ alkyl, R⁷ is H orC₁-C₅ alkyl, R⁸ is H, hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl; each R⁹and R¹⁰ is hydrogen; and Q is unsubstituted pyridyl; or pyridylsubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl,carboxyl and —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ is independently Hor optionally substituted C₁-C₅ alkyl;

(30) n is 0 and m is 1; R¹ is H or CH₃; R⁷ is H or CH₃; and R⁸ is H orhydroxyl;

(31) X is N; R¹ is H or C₁-C₅ alkyl, R⁷ is H or C₁-C₅ alkyl, R⁸ is H,hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl; each R⁹ and R¹⁰ is hydrogen;and Q is unsubstituted pyridyl; or pyridyl substituted with 1 to 3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷,wherein each R¹⁶ and R¹⁷ is independently H or optionally substitutedC₁-C₅ alkyl;

(32) n is 0 and m is 1; R¹ is H or CH₃; R⁷ is H or CH₃; and R⁸ is H orhydroxyl;

(33) n is 0 and m is 1; R¹ is taken together with R^(2a) to form apropylene (—CH₂CH₂CH₂—) moiety; X is CR^(6a), wherein R^(6a) is H, haloor C₁-C₅ alkyl; each R⁶ is independently H, halo or C₁-C₅ alkyl; R⁷ is Hor C₁-C₅ alkyl, R⁸ is H, hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl; eachR⁹ and R¹⁰ is hydrogen; and Q is unsubstituted pyridyl; or pyridylsubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl,carboxyl and —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ is independently Hor optionally substituted C₁-C₅ alkyl; and

(34) R⁷ is H or CH₃; and R⁸ is H or hydroxyl.

In some embodiments, the compound used in the methods described hereinis a compound of formula (A-IIIA) detailed herein, wherein any one ormore of provisions (35)-(45) apply:

(35) X is CH;

(36) X is N;

(37) R¹ is H or CH₃;

(38) R^(2a) is H or is taken together with R¹ to form a propylene(—CH₂CH₂CH₂—) moiety;

(39) each R⁶ and R^(6a) is independently H, halo or C₁-C₅ alkyl;

(40) R⁷ is H or CH₃;

(41) R⁸ is hydroxyl;

(42) Q is: unsubstituted pyridyl; unsubstituted pyrimidyl; unsubstitutedpyrazinyl; unsubstituted phenyl; pyridyl substituted with halo, CH₃,CF₃, CONH₂, OH, or OCH₃; pyrimidyl substituted with halo, CH₃, CF₃,CONH₂, OH, or OCH₃; pyrazinyl substituted with halo, CH₃, CF₃, CONH₂,OH, or OCH₃; or phenyl substituted with halo, CH₃, CF₃, CONH₂, OH, orOCH₃;

(43) Q is: unsubstituted pyridyl; unsubstituted pyrimidyl; unsubstitutedpyrazinyl; unsubstituted phenyl; unsubstituted imidazolyl; unsubstitutedtriazolyl; pyridyl substituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃;pyrimidyl substituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃; pyrazinylsubstituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃; or phenylsubstituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃;

(44) X is CH; R¹ is H or CH₃; each R⁶ is independently H, halo or C₁-C₅alkyl; R⁷ is H or CH₃; R⁸ is hydroxyl; and Q is unsubstituted pyridyl,or pyridyl substituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃; and

(45) R¹ is CH₃; R⁶ is CH₃; and Q is unsubstituted pyridyl.

In another embodiment, with respect to the methods of the invention, thecompound binds to and is an antagonist of the adrenergic receptor α_(2A)and, wherein the compound either (a) also binds to and is an antagonistof the adrenergic receptor α_(2B) or (b) the compound is not anantagonist of the adrenergic receptor α_(2B) and the compound isadministered in conjunction with a second agent that reduces bloodpressure in the individual. In one embodiment, the compound binds to andis an antagonist of the adrenergic receptor α_(2B). In anotherembodiment, the compound binds to and is an antagonist of the adrenergicreceptor α_(1B). In another embodiment, the compound is not anantagonist of the adrenergic receptor α_(2B) and the compound isadministered in conjunction with a diuretic, an angiotensin-convertingenzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist, a betablocker, a calcium channel blocker, or any combination thereof.

Also provided is a kit comprising (i) a compound of formula (I) or anyvariations detailed herein, or a pharmaceutically acceptable saltthereof, and (ii) instructions for use according to the methods ofdescribed herein. Further provided is a kit comprising a compound offormula (A-IIIA) or any variations detailed herein, or apharmaceutically acceptable salt thereof, and (ii) instructions for useaccording to the method described herein.

Also provided is use of a compound detailed herein, such as a compoundof formula (I) or any variations thereof, or a salt, solvate or N-oxidethereof, in regulating (reducing and/or stabilizing) blood glucose,increasing insulin secretion, and/or promoting insulin release in theblood stream. Further provided are uses of a compound detailed herein,such as a compound of formula (I) or any variations thereof, or a salt,solvate or N-oxide thereof, for the manufacturing of a medicament forthe treatment of a disease or condition that is responsive to anincrease in insulin secretion, such as type 2 diabetes, glucoseintolerance and metabolic syndrome.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the effects of Compound No. 129d on blood glucoselevels in clonidine induced hyperglycemic SHR.OB rats. The term“Compound” may be defined as “Cpd” in the Figures.

FIG. 2 illustrates the effects of Compound No. 129d on blood glucoselevels in clonidine induced hyperglycemic Wistar rats.

FIG. 3 illustrates the effects of Compound No. 129d on blood glucoselevels in norepinephrine induced hyperglycemic SHR.OB rats.

FIG. 4 illustrates the effects of Compound No. 129d on blood glucoselevels in norepinephrine induced hyperglycemic Wistar rats.

FIG. 5 illustrates the effects of Compound No. 129d on blood glucoselevels in normoglycemic SHR.OB rats.

FIG. 6 illustrates the effect of Compound No. 129d on insulin levels(competition with clonidine) [With 0% as the insulin secreted at lowglucose (LG) and 100% the insulin secreted at high glucose (HG)].

FIG. 7 illustrates the effect of Compound No. 129d on insulin levels(competition with norepinephrine) [With 0% as the insulin secreted atlow glucose (LG) and 100% the insulin secreted at high glucose (HG)].

FIG. 8 illustrates the effect of Compound No. 129d withNateglinide/Meglitinide induced insulin release in pancreatic beta cellmodel.

FIG. 9 illustrates the effect of Compound No. 129d on blood glucoselevels in norepinephrine induced hyperglycemic SHR.OB rats.

FIG. 10 illustrates the effect of Compound No. 129d on serum insulinlevels in norepinephrine induced hyperglycemic SHR.OB rats.

FIG. 11 illustrates the effect of Compound No. 129d on blood glucoselevels in norepinephrine induced hyperglycemic Wistar rats.

FIG. 12 illustrates the effect of Compound No. 129d on serum insulinlevels in norepinephrine induced hyperglycemic Wistar rats.

FIG. 13 illustrates the effect of Compound No. 129d on blood glucoselevels in norepinephrine induced hyperglycemic ob/ob mice.

FIG. 14 illustrates the effect of Compound No. 129d on serum insulinlevels in norepinephrine induced hyperglycemic ob/ob mice.

FIG. 15 illustrates the effect of Compound No. 129d on blood glucoselevels in spontaneously hyperglycemic ob/ob mice (No NE challenge).

FIG. 16 illustrates the effect of Compound No. 129d on serum insulinlevels in spontaneously hyperglycemic ob/ob mice (No NE challenge).

FIG. 17 illustrates the effect of Compound No. 129d on blood glucoselevels in glucose challenged hyperglycemic (OGTT) SHR.OB rats.

FIG. 18 illustrates the effect of Compound No. 129d on serum insulinlevels in glucose challenged hyperglycemic (OGTT) SHR.OB rats.

FIG. 19 illustrates the effect of Compound No. 129d (oral) on systolicblood pressure in SHR rats.

FIG. 20 illustrates the effect of Compound No. 129d (i.v., bolus) onsystolic blood pressure in SHR rats.

FIG. 21 illustrates the effect of Compound No. 129d (i.v., escalatingdoses) on systolic blood pressure in SHR rats.

FIG. 22 illustrates Compound No. 129d in a human adrenergic a2A receptorinverse agonist activity (using GTPg35S binding functional) assay.

FIG. 23 illustrates the synergistic effect of Compound No. 129d withglibenclamide in rat pancreatic islets.

FIG. 24 illustrates the synergistic effect of Compound No. 129d withglimepiride in rat pancreatic islets.

FIG. 25 illustrates that Compound No. 129d blocks pERK1/2 norepinephrinemediated effects in rat pancreatic islets.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless clearly indicated otherwise, the terms “a,” “an,” and the like,refer to one or more.

It is also understood and clearly conveyed by this disclosure thatreference to “the compound” or “a compound” includes and refers to anycompounds (e.g., selective adrenergic receptor α_(2B) antagonists) orpharmaceutically acceptable salt or other form thereof as describedherein.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a human. The inventionmay find use in both human medicine and in the veterinary context.

As used herein, an “at risk” individual is an individual who is at riskof developing a disease or condition. An individual “at risk” may or maynot have a detectable disease or condition, and may or may not havedisplayed detectable disease prior to the treatment methods describedherein. “At risk” denotes that an individual has one or more so-calledrisk factors, which are measurable parameters that correlate withdevelopment of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s).

As used herein, “treatment” or “treating” is an approach for obtaining abeneficial or desired result, including clinical results.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition.

As used herein, the term “effective amount” intends such amount of acompound of the invention which should be effective in a giventherapeutic form. As is understood in the art, an effective amount maybe in one or more doses, i.e., a single dose or multiple doses may berequired to achieve the desired treatment endpoint. An effective amountmay be considered in the context of administering one or moretherapeutic agents, and a single agent may be considered to be given inan effective amount if, in conjunction with one or more other agents, adesirable or beneficial result may be or is achieved. Suitable doses ofany of the co-administered compounds may optionally be lowered due tothe combined action (e.g., additive or synergistic effects) of thecompounds.

As used herein, “unit dosage form” refers to physically discrete units,suitable as unit dosages, each unit containing a predetermined quantityof active ingredient, or compound which may be in a pharmaceuticallyacceptable carrier.

As used herein, by “pharmaceutically acceptable” is meant a materialthat is not biologically or otherwise undesirable, e.g., the materialmay be incorporated into a pharmaceutical composition administered to anindividual without causing significant undesirable biological effects orinteracting in a deleterious manner with any of the other components ofthe composition in which it is contained. Pharmaceutically acceptablecarriers or excipients have preferably thus in some embodiments met therequired standards of toxicological and manufacturing testing and/or areincluded on the Inactive Ingredient Guide prepared by the U.S. Food andDrug administration.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. Such salts, for example, include: (1) acid addition salts,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, oxalic acid, propionic acid,succinic acid, maleic acid, tartaric acid and the like; (2) salts formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion,or an aluminum ion; or coordinates with an organic base. Acceptableorganic bases include ethanolamine, diethanolamine, triethanolamine andthe like. Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like. Further examples of pharmaceutically acceptable salts includethose listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977January; 66(1):1-19. Pharmaceutically acceptable salts can be preparedin situ in the manufacturing process, or by separately reacting apurified compound of the invention in its free acid or base form with asuitable organic or inorganic base or acid, respectively, and isolatingthe salt thus formed during subsequent purification. It should beunderstood that a reference to a pharmaceutically acceptable saltincludes the solvent addition forms or crystal forms thereof,particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and are oftenformed during the process of crystallization. Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. Polymorphs include the different crystal packing arrangementsof the same elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature may cause asingle crystal form to dominate.

The term “excipient” as used herein includes an inert or inactivesubstance that may be used in the production of a drug orpharmaceutical, such as a tablet containing a compound detailed herein,or a pharmaceutically acceptable salt thereof, as an active ingredient.Various substances may be embraced by the term excipient, includingwithout limitation any substance used as a binder, disintegrant,coating, compression/encapsulation aid, cream or lotion, lubricant,solutions for parenteral administration, materials for chewable tablets,sweetener or flavoring, suspending/gelling agent, or wet granulationagent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;coatings include, e.g., cellulose acetate phthalate, ethylcellulose,gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

An inverse agonist is a compound that binds to a receptor and inhibitsthe activity of the receptor in the absence of an agonist. An inverseagonist requires that the receptor have some constitutive basal activityin the absence of an agonist. While an agonist increases activity of thereceptor over basal level an inverse agonist reduces receptor activitybelow basal level.

“Alkyl” refers to and includes saturated linear, branched, or cyclicunivalent hydrocarbon structures and combinations thereof. Particularalkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀ alkyl”).More particular alkyl groups are those having 1 to 8 carbon atoms (a“C₁-C₈ alkyl”). When an alkyl residue having a specific number ofcarbons is named, all geometric isomers having that number of carbonsare intended to be encompassed and described; thus, for example, “butyl”is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl andcyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. Thisterm is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl,cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset ofalkyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as adamantyl. A cycloalkyl comprising more than one ring maybe fused, spiro or bridged, or combinations thereof. A preferredcycloalkyl is a saturated cyclic hydrocarbon having from 3 to 13 annularcarbon atoms. A more preferred cycloalkyl is a saturated cyclichydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkyl”). Examples of cycloalkyl groups include adamantyl,decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland the like.

“Alkylene” refers to the same residues as alkyl, but having bivalency.Examples of alkylene include methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—) and the like.

“Alkenyl” refers to an unsaturated hydrocarbon group having at least onesite of olefinic unsaturation (i.e., having at least one moiety of theformula C═C) and preferably having from 2 to carbon atoms and morepreferably 2 to 8 carbon atoms. Examples of alkenyl include but are notlimited to —CH₂—CH═CH—CH₃ and —CH₂—CH₂-cyclohexenyl, where the ethylgroup of the latter example can be attached to the cyclohexenyl moietyat any available position on the ring. Cycloalkenyl is a subset ofalkenyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as norbornenyl. A more preferred cycloalkenyl is anunsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms(a “C₃-C₈ cycloalkenyl”). Examples of cycloalkenyl groups includecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.

“Alkynyl” refers to an unsaturated hydrocarbon group having at least onesite of acetylenic unsaturation (i.e., having at least one moiety of theformula C≡C) and preferably having from 2 to carbon atoms and morepreferably 2 to 8 carbon atoms and the like.

“Substituted alkyl” refers to an alkyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkenyl” refers to alkenyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, cycloalkyl-C(O)—,substituted cycloalkyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O)—, heterocyclic-C(O)—, and substitutedheterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—,heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—,and substituted heterocyclic-C(O)O—, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturatedor an unsaturated non-aromatic group having a single ring or multiplecondensed rings, and having from 1 to 10 annular carbon atoms and from 1to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and thelike. A heterocycle comprising more than one ring may be fused, spiro orbridged, or any combination thereof. In fused ring systems, one or moreof the rings can be aryl or heteroaryl. A heterocycle having more thanone ring where at least one ring is aromatic may be connected to theparent structure at either a non-aromatic ring position or at anaromatic ring position. In one variation, a heterocycle having more thanone ring where at least one ring is aromatic is connected to the parentstructure at a non-aromatic ring position.

“Substituted heterocyclic” or “substituted heterocyclyl” refers to aheterocycle group which is substituted with from 1 to 3 substituentsincluding, but not limited to, substituents such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like. In one variation, a substitutedheterocycle is a heterocycle substituted with an additional ring,wherein the additional ring may be aromatic or non-aromatic.

“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic grouphaving a single ring (e.g., phenyl) or multiple condensed rings (e.g.,naphthyl or anthryl) which condensed rings may or may not be aromatic.In one variation, the aryl group contains from 6 to 14 annular carbonatoms. An aryl group having more than one ring where at least one ringis non-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, an aryl group having more than one ring where at least onering is non-aromatic is connected to the parent structure at an aromaticring position.

“Heteroaryl” or “HetAr” refers to an unsaturated aromatic carbocyclicgroup having from 1 to 10 annular carbon atoms and at least one annularheteroatom, including but not limited to heteroatoms such as nitrogen,oxygen and sulfur. A heteroaryl group may have a single ring (e.g.,pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl,benzothienyl) which condensed rings may or may not be aromatic. Aheteroaryl group having more than one ring where at least one ring isnon-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, a heteroaryl group having more than one ring where at leastone ring is non-aromatic is connected to the parent structure at anaromatic ring position.

“Substituted aryl” refers to an aryl group having 1 to 5 substituentsincluding, but not limited to, groups such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy andthe like.

“Substituted heteroaryl” refers to a heteroaryl group having 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like.

“Aralkyl” refers to a residue in which an aryl moiety is attached to analkyl residue and wherein the aralkyl group may be attached to theparent structure at either the aryl or the alkyl residue. Preferably, anaralkyl is connected to the parent structure via the alkyl moiety. Inone variation, an aralkyl is a fused ring system where at least onecycloalkyl moiety is fused with at least one aryl moiety. A “substitutedaralkyl” refers to a residue in which an aryl moiety is attached to asubstituted alkyl residue and wherein the aralkyl group may be attachedto the parent structure at either the aryl or the alkyl residue. When anaralkyl is connected to the parent structure via the alkyl moiety, itmay also be referred to as an “alkaryl”. More particular alkaryl groupsare those having 1 to 3 carbon atoms in the alkyl moiety (a “C₁-C₃alkaryl”).

“Alkoxy” refers to the group alkyl-O—, which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.Similarly, alkenyloxy refers to the group “alkenyl-O—” and alkynyloxyrefers to the group “alkynyl-O—”. “Substituted alkoxy” refers to thegroup substituted alkyl-O.

“Unsubstituted amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR_(a)R_(b), where either (a)each R_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, providedthat both R_(a) and R_(b) groups are not H; or (b) R_(a) and R_(b) arejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Acylamino” refers to the group —C(O)NR_(a)R_(b) where R_(a) and R_(b)are independently selected from the group consisting of H, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic or R_(a) and R_(b) groups can bejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Aminoacyl” refers to the group —NR_(a)C(O)R_(b) where each R_(a) andR_(b) group is independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic or substituted heterocyclic. Preferably, R_(a)is H or alkyl.

“Aminosulfonyl” refers to the groups —NRSO₂-alkyl, —NRSO₂ substitutedalkyl, —NRSO₂-alkenyl, —NRSO₂-substituted alkenyl, —NRSO₂-alkynyl,—NRSO₂-substituted alkynyl, —NRSO₂-cycloalkyl, —NRSO₂-substitutedcycloalkyl, —NRSO₂-aryl, —NRSO₂-substituted aryl, —NRSO₂-heteroaryl,—NRSO₂-substituted heteroaryl, —NRSO₂-heterocyclic, and—NRSO₂-substituted heterocyclic, where R is H or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the groups —SO₂NH₂, —SO₂NR-alkyl,—SO₂NR-substituted alkyl, —SO₂NR-alkenyl, —SO₂NR-substituted alkenyl,—SO₂NR-alkynyl, —SO₂NR-substituted alkynyl, —SO₂NR-aryl,—SO₂NR-substituted aryl, —SO₂NR-heteroaryl, —SO₂NR-substitutedheteroaryl, —SO₂NR-heterocyclic, and —SO₂NR-substituted heterocyclic,where R is H or alkyl, or —SO₂NR₂, where the two R groups are takentogether and with the nitrogen atom to which they are attached to form aheterocyclic or substituted heterocyclic ring.

“Sulfonyl” refers to the groups —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substitutedalkynyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-aralkyl,—SO₂-substituted aralkyl, —SO₂-heteroaryl, —SO₂-substituted heteroaryl,—SO₂-heterocyclic, and —SO₂-substituted heterocyclic.

“Aminocarbonylalkoxy” refers to the group —NR_(a)C(O)OR_(b) where eachR_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclyl.

“Carbonylalkylenealkoxy” refers to the group —C(O)—(CH₂)_(n)—OR where Ris a substituted or unsubstituted alkyl and n is an integer from 1 to100, more preferably n is an integer from 1 to 10 or 1 to 5.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include the radicals offluorine, chlorine, bromine and iodine. Where a residue is substitutedwith more than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached, e.g.,dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may bebut are not necessarily the same halogen; thus 4-chloro-3-fluorophenylis within the scope of dihaloaryl. An alkyl group in which each H isreplaced with a halo group is referred to as a “perhaloalkyl.” Apreferred perhaloalkyl group is trifluoroalkyl (—CF₃). Similarly,“perhaloalkoxy” refers to an alkoxy group in which a halogen takes theplace of each H in the hydrocarbon making up the alkyl moiety of thealkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy(—OCF₃).

“Carbonyl” refers to the group C═O.

“Cyano” refers to the group —CN.

“Oxo” refers to the moiety ═O.

“Nitro” refers to the group —NO₂.

“Thioalkyl” refers to the groups —S-alkyl.

“Alkylsulfonylamino” refers to the groups —R¹SO₂NR_(a)R_(b) where R_(a)and R_(b) are independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, or the R_(a) andR_(b) groups can be joined together with the nitrogen atom to form aheterocyclic or substituted heterocyclic ring and R¹ is an alkyl group.

“Carbonylalkoxy” refers to as used herein refers to the groups—C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substitutedaryl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic or —C(O)O-substituted heterocyclic.

“Geminal” refers to the relationship between two moieties that areattached to the same atom. For example, in the residue —CH₂—CHR¹R², R¹and R² are geminal and R¹ may be referred to as a geminal R group to R².

“Vicinal” refers to the relationship between two moieties that areattached to adjacent atoms. For example, in the residue —CHR¹—CH₂R², R¹and R² are vicinal and R¹ may be referred to as a vicinal R group to R².

A composition of “substantially pure” compound means that thecomposition contains no more than 15% or preferably no more than 10% ormore preferably no more than 5% or even more preferably no more than 3%and most preferably no more than 1% impurity, which impurity may be thecompound in a different stereochemical form. For instance, a compositionof substantially pure (S) compound means that the composition containsno more than 15% or no more than 10% or no more than 5% or no more than3% or no more than 1% of the (R) form of the compound.

Receptor Binding Profile

In some embodiments, compounds provided herein bind to and areantagonists of the adrenergic receptor α_(2A). In one variation,compounds provided herein bind to and are antagonists of the adrenergicreceptor α_(2A) and either (a) also bind to and are antagonists of theadrenergic receptor α_(2B) or (b) are not antagonists of the adrenergicreceptor α_(2B) but are administered in the methods detailed herein inconjunction with a second agent that reduces, or is expected to reduce,blood pressure in an individual. By exhibiting the dual properties ofbinding to and being an antagonist of both the adrenergic receptorα_(2A) and the adrenergic receptor α_(2B), compounds provided herein mayexert the beneficial effect of increasing insulin secretion and/orpromoting insulin release in an individual while reducing or eliminatingthe side effect of an increase in blood pressure that may be associatedwith antagonizing the adrenergic receptor α_(2A). Alternatively,compounds provided herein that bind to and are antagonists of theadrenergic receptor α_(2A), but which do not bind to and are notantagonists of the adrenergic receptor α_(2B), may be used in therapy inconjunction with a second agent that reduces, or is expected to reduce,blood pressure in an individual, thereby allowing the adrenergicreceptor α_(2A) antagonist to exert its therapeutic effects whilereducing or eliminating the side effect of an increase in blood pressurethat may be associated with antagonizing the adrenergic receptor α_(2A).Thus, it is understood that a second compound that reduces, or isexpected to reduce, blood pressure in an individual includes a secondcompound that reduces or prevents an increase in an individual's bloodpressure associated with antagonizing the adrenergic receptor α_(2A). Itis further understood that any of the compounds provided herein may beadministered in conjunction with a second agent that reduces, or isexpected to reduce, blood pressure in an individual. For example, such acombination therapy may be utilized in an individual who has high bloodpressure or has a propensity toward high blood pressure that is notassociated with being administered a compound that antagonizes theadrenergic receptor α_(2A). Compounds that exhibit the dual propertiesof binding to and being an antagonist of both the adrenergic receptorα_(2A) and the adrenergic receptor α_(2B) may also be administered inconjunction with a second agent that reduces, or is expected to reduce,blood pressure in an individual.

Compounds that antagonize the adrenergic receptor α_(2A) and theadrenergic receptor α_(2B) may lower blood glucose and reduce bloodpressure and be of therapeutic utility in individuals with high glucoseand high blood pressure, for example individuals who have metabolicsyndrome. Compounds that antagonize the adrenergic receptor α_(2A) andthe adrenergic receptor α_(2B) may also block the adrenergic receptorα_(1B) and have utility in individuals with high blood glucose and highblood pressure.

The compounds provided herein may in some embodiments also bind to andbe antagonists of the adrenergic receptor α_(1B), which activity mayalso help reduce or eliminate an increase in blood pressure in anindividual in response to a compound that is an adrenergic receptorα_(2A) antagonist. Thus, in one variation, compounds that bind to andare antagonists of the adrenergic receptor α_(2A) are provided, whereinthe compounds also bind to and are antagonists of the adrenergicreceptors α_(2B) and α_(1B). In another variation, compounds that bindto and are antagonists of the adrenergic receptor α_(2A) are provided,wherein the compounds also bind to and are antagonists of the adrenergicreceptor α_(1B) but which are not antagonists of the adrenergic receptorα_(2B). Such compounds, when are administered in the methods detailedherein, may be administered in conjunction with a second agent thatreduces, or is expected to reduce, blood pressure in an individual.

The compounds provided herein may in some embodiments also bind to andbe antagonists of the adrenergic receptor α_(1D), which activity mayalso help reduce or eliminate an increase in blood pressure in anindividual in response to a compound that is an adrenergic receptorα_(2A) antagonist. Thus, in one variation, compounds that bind to andare antagonists of the adrenergic receptor α_(2A) are provided, whereinthe compounds also bind to and are antagonists of the adrenergicreceptors α_(2B), α_(1B) and α_(1D). In another variation, compoundsthat bind to and are antagonists of the adrenergic receptor α_(2A) areprovided, wherein the compounds also bind to and are antagonists of theadrenergic receptor α_(1B) and α_(1D) but which are not antagonists ofthe adrenergic receptor α_(2B). In another variation, compounds thatbind to and are antagonists of the adrenergic receptor α_(2A) areprovided, wherein the compounds also bind to and are antagonists of theadrenergic receptor α_(2B) and α_(1D) but which are not antagonists ofthe adrenergic receptor α_(1B). In another variation, compounds thatbind to and are antagonists of the adrenergic receptor α_(2A) areprovided, wherein the compounds also bind to and are antagonists of theadrenergic receptors α_(1D), but which are not antagonists of theadrenergic receptor α_(2B) or α_(1B). Such compounds, when administeredin the methods detailed herein, may be administered in conjunction witha second agent that reduces, or is expected to reduce, blood pressure inan individual.

The second agent that reduces, or is expected to reduce, blood pressurein an individual may be a diuretic, an angiotensin-converting enzyme(ACE) inhibitor, an angiotensin-2 receptor antagonist, a beta blocker, acalcium channel blocker, or any combination thereof. In one variation,the second agent that reduces, or is expected to reduce, blood pressurein an individual is a compound that binds to and is an antagonist of theadrenergic receptor α_(2B) but which is not an antagonist of theadrenergic receptor α_(2A). In one variation, the second agent is asingle compound. However, it is understood that the second agent in oneembodiment may be two or more compounds, such as a second agent thatcomprises a first compound that is a diuretic and a second compound thatis an ACE-inhibitor.

In one variation, a compound provided herein exhibits equal to orgreater than about 50% inhibition of α_(2A) ligand binding at 0.1 μM andantagonist activity to adrenergic receptor α_(2A). In one variation, acompound provided herein exhibits greater than or equal to about any oneof 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% or between about50% and about 90% or between about 60% and about 90% or between about70% and about 90% or between about 80% and about 100% inhibition ofα_(2A) ligand binding at 0.1 μM and antagonist activity to adrenergicreceptor α_(2A). In one variation, a compound provided herein exhibitsequal to or greater than about 50% inhibition of α_(2A) ligand bindingat 0.03 μM and antagonist activity to adrenergic receptor α_(2A). In onevariation, a compound provided herein exhibits greater than or equal toabout any one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% orbetween about 50% and about 90% or between about 60% and about 90% orbetween about 70% and about 90% or between about 80% and about 100%inhibition of α_(2A) ligand binding at 0.03 μM and antagonist activityto adrenergic receptor α_(2A).

In another variation, a compound as provided herein (i) binds to and isan antagonist of adrenergic receptor α_(2A) and (ii) exhibits greaterthan or equal to about 50% inhibition of α_(2B) ligand binding at 0.1 μMand antagonist activity to adrenergic receptor α_(2B). In one suchvariation, a compound as provided herein exhibits (i) greater than orequal to about 50% inhibition of α_(2A) ligand binding at 0.1 μM andantagonist activity to adrenergic receptor α_(2A) and (ii) greater thanor equal to about 50% inhibition of α_(2B) ligand binding at 0.1 μM andantagonist activity to adrenergic receptor α_(2B). When the compoundexhibits greater than or equal to about 50% inhibition of α_(2B) ligandbinding at 0.1 μM and antagonist activity to adrenergic receptor α_(2B),in some embodiments, it exhibits greater than or equal to about any oneof 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% or between about50% and about 90% or between about 60% and about 90% or between about70% and about 90% or between about 80% and about 100% inhibition ofα_(2B) ligand binding at 0.1 μM and antagonist activity to adrenergicreceptor α_(2B). In another variation, a compound as provided hereinexhibits (i) greater than or equal to about 50% inhibition of α_(2A)ligand binding at 0.03 μM and antagonist activity to adrenergic receptorα_(2A) and (ii) greater than or equal to about 50% inhibition of α_(2B)ligand binding at 0.03 μM and antagonist activity to adrenergic receptorα_(2B). In another variation, a compound as provided herein exhibits (i)greater than or equal to about 50% inhibition of α_(2A) ligand bindingat 0.03 μM and antagonist activity to adrenergic receptor α_(2A) and(ii) greater than or equal to about 50% inhibition of α_(2B) ligandbinding at 0.1 μM and antagonist activity to adrenergic receptor α_(2B).In another variation, a compound as provided herein exhibits (i) greaterthan or equal to about 50% inhibition of α_(2A) ligand binding at 0.1 μMand antagonist activity to adrenergic receptor α_(2A) and (ii) greaterthan or equal to about 50% inhibition of α_(2B) ligand binding at 0.03μM and antagonist activity to adrenergic receptor α_(2B). When thecompound exhibits greater than or equal to about 50% inhibition ofα_(2B) ligand binding at 0.03 μM and antagonist activity to adrenergicreceptor α_(2B), in some embodiments, it exhibits greater than or equalto about any one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%or between about 50% and about 90% or between about 60% and about 90% orbetween about 70% and about 90% or between about 80% and about 100%inhibition of α_(2B) ligand binding at 0.03 μM and antagonist activityto adrenergic receptor α_(2B). It is understood and clearly conveyedherein that an adrenergic receptor α_(2A) antagonist can exhibit any ofthe adrenergic receptor α_(2A) binding profiles described herein incombination with any of the adrenergic receptor α_(2B) binding profilesdescribed herein, as if each and every combination were listedseparately.

The adrenergic receptor α_(2A) antagonists may also be used inconjunction with other agents that antagonize the adrenergic receptorα_(2B). Administration in conjunction with another compound includesadministration in the same or different composition, eithersequentially, simultaneously, or continuously.

In one variation, compounds provided herein that bind to and areantagonists of the adrenergic receptor α_(2A) will also bind to andantagonize the adrenergic receptor α_(1B). In another variation,compounds provided herein that bind to and are antagonists of theadrenergic receptor α_(2A) and either (a) also bind to and areantagonists of the adrenergic receptor α_(2B) or (b) are administered inthe methods detailed herein in conjunction with a second agent thatreduces, or is expected to reduce, blood pressure in an individual, willalso bind to and antagonize the adrenergic receptor α_(1B). In someembodiments, compounds provided herein may exhibit greater than or equalto about 50% inhibition of α_(1B) ligand binding at 0.1 μM andantagonist activity to adrenergic receptor α_(1B). In some embodiments,compounds provided herein may exhibit greater than or equal to about anyone of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or betweenabout 50% and about 90%, between about 60% and about 90%, between about70% and about 90%, or between about 80% and about 100% inhibition ofα_(1B) ligand binding at 0.1 μM and antagonist activity to adrenergicreceptor α_(1B). In some embodiments, compounds provided herein mayexhibit greater than or equal to about 50% inhibition of α_(1B) ligandbinding at 0.03 μM and antagonist activity to adrenergic receptorα_(1B). In some embodiments, compounds provided herein may exhibitgreater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, or 95%, or between about 50% and about 90%, between about60% and about 90%, between about 70% and about 90%, or between about 80%and about 100% inhibition of α_(1B) ligand binding at 0.03 μM andantagonist activity to adrenergic receptor α_(1B). For example, in onevariation, a compound provided herein exhibits equal to or greater thanabout 50% inhibition of α_(2A) ligand binding at 0.1 μM and antagonistactivity to adrenergic receptor α_(2A) and greater than or equal toabout 50% inhibition of α_(1B) ligand binding at 0.1 μM and antagonistactivity to adrenergic receptor α_(1B). In another variation, a compoundprovided herein exhibits equal to or greater than about 50% inhibitionof α_(2A) ligand binding at 0.1 μM and antagonist activity to adrenergicreceptor α_(2A), greater than or equal to about 50% inhibition of α_(2B)ligand binding at 0.1 μM and antagonist activity to adrenergic receptorα_(2B) and greater than or equal to about 50% inhibition of α_(1B)ligand binding at 0.1 μM and antagonist activity to adrenergic receptorα_(1B). In one variation, a compound provided herein exhibits equal toor greater than about 50% inhibition of α_(2A) ligand binding at 0.1 μMand antagonist activity to adrenergic receptor α_(2A), greater than orequal to about 50% inhibition of α_(2B) ligand binding at 0.1 μM andantagonist activity to adrenergic receptor α_(2B) and greater than orequal to about any one of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,or 95%, or between about 50% and about 90%, between about 60% and about90%, between about 70% and about 90%, or between about 80% and about100% inhibition of α_(1B) ligand binding at 0.1 μM and antagonistactivity to adrenergic receptor α_(1B). It is understood and clearlyconveyed herein that an adrenergic receptor α_(2A) antagonist canexhibit any of the adrenergic receptor α_(2A) binding profiles describedherein in combination with any of the adrenergic receptor α_(2B) bindingprofiles described herein, and/or any of the adrenergic receptor α_(1B)binding profiles described herein as if each and every combination werelisted separately.

The adrenergic receptor α_(2A) antagonists may also be used inconjunction with other agents that antagonize the adrenergic receptorα_(1B). Administration in conjunction with another compound includesadministration in the same or different composition, eithersequentially, simultaneously, or continuously.

In one variation, compounds provided herein that bind to and areantagonists of the adrenergic receptor α_(2A) will also bind to andantagonize the adrenergic receptor α_(1D). In another variation,compounds provided herein that bind to and are antagonists of theadrenergic receptor α_(2A) and either (a) also bind to and areantagonists of the adrenergic receptor α_(2B) or (b) are administered inthe methods detailed herein in conjunction with a second agent thatreduces, or is expected to reduce, blood pressure in an individual, willalso bind to and antagonize the adrenergic receptor α_(1D). In anothervariation, compounds provided herein that bind to and are antagonists ofthe adrenergic receptor α_(2A) and either (a) also bind to and areantagonists of the adrenergic receptor α_(2B) or (b) are administered inthe methods detailed herein in conjunction with a second agent thatreduces, or is expected to reduce, blood pressure in an individual, andbind to and are antagonists of the adrenergic receptor α_(1B) will alsobind to and antagonize the adrenergic receptor α_(1D). In someembodiments, compounds provided herein may exhibit greater than or equalto about 50% inhibition of α_(1D) ligand binding at 0.1 μM andantagonist activity to adrenergic receptor α_(1D). In some embodiments,compounds provided herein may exhibit greater than or equal to about anyone of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or betweenabout 50% and about 90%, between about 60% and about 90%, between about70% and about 90%, or between about 80% and about 100% inhibition ofα_(1D) ligand binding at 0.1 μM and antagonist activity to adrenergicreceptor α_(1D). In some embodiments, compounds provided herein mayexhibit greater than or equal to about 50% inhibition of α_(1D) ligandbinding at 0.03 μM and antagonist activity to adrenergic receptorα_(1D). In some embodiments, compounds provided herein may exhibitgreater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 90%, or 95%, or between about 50% and about 90%, between about60% and about 90%, between about 70% and about 90%, or between about 80%and about 100% inhibition of α_(1D) ligand binding at 0.03 μM andantagonist activity to adrenergic receptor α_(1D). For example, in onevariation, a compound provided herein exhibits equal to or greater thanabout 50% inhibition of α_(2A) ligand binding at 0.1 μM and antagonistactivity to adrenergic receptor α_(2A) and greater than or equal toabout 50% inhibition of α_(1D) ligand binding at 0.1 μM and antagonistactivity to adrenergic receptor α_(1D). In another variation, a compoundprovided herein exhibits equal to or greater than about 50% inhibitionof α_(2A) ligand binding at 0.1 μM and antagonist activity to adrenergicreceptor α_(2A), greater than or equal to about 50% inhibition of α_(2B)ligand binding at 0.1 μM and antagonist activity to adrenergic receptorα_(2B) and greater than or equal to about 50% inhibition of α_(1D)ligand binding at 0.1 μM and antagonist activity to adrenergic receptorα_(1D). In another variation, a compound provided herein exhibits equalto or greater than about 50% inhibition of α_(2A) ligand binding at 0.1μM and antagonist activity to adrenergic receptor α_(2A), greater thanor equal to about 50% inhibition of α_(2B) ligand binding at 0.1 μM andantagonist activity to adrenergic receptor α_(2B), greater than or equalto about 50% inhibition of α_(1B) ligand binding at 0.1 μM andantagonist activity to adrenergic receptor α_(1B), and greater than orequal to about 50% inhibition of α_(1D) ligand binding at 0.1 μM andantagonist activity to adrenergic receptor α_(1D). In one variation, acompound provided herein exhibits equal to or greater than about 50%inhibition of α_(2A) ligand binding at 0.1 μM and antagonist activity toadrenergic receptor α_(2A), greater than or equal to about 50%inhibition of α_(2B) ligand binding at 0.1 μM and antagonist activity toadrenergic receptor α_(2B), greater than or equal to about 50%inhibition of α_(1B) ligand binding at 0.1 μM and antagonist activity toadrenergic receptor α_(1B) and greater than or equal to about any one of50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or between about50% and about 90%, between about 60% and about 90%, between about 70%and about 90%, or between about 80% and about 100% inhibition of α_(1D)ligand binding at 0.1 μM and antagonist activity to adrenergic receptorα_(1D). It is understood and clearly conveyed herein that an adrenergicreceptor α_(2A) antagonist can exhibit any of the adrenergic receptorα_(2A) binding profiles described herein in combination with any of theadrenergic receptor α_(2B) binding profiles described herein, and/or anyof the adrenergic receptor α_(1B) binding profiles described hereinand/or any of the adrenergic receptor α_(1D) binding profiles describedherein as if each and every combination were listed separately.

The adrenergic receptor α_(2A) antagonists may also be used inconjunction with other agents that antagonize the adrenergic receptorα_(1D). Administration in conjunction with another compound includesadministration in the same or different composition, eithersequentially, simultaneously, or continuously.

The binding properties to adrenergic receptors of compounds disclosedherein may be assessed by methods known in the art, such as competitivebinding assays. In one variation, compounds are assessed by the bindingassays detailed herein. In one variation, inhibition of binding of aligand to a receptor is measured by the assays described herein. Inanother variation, inhibition of binding of a ligand is measured in anassay known in the art.

Functional Assay Profile

Antagonist activity to the adrenergic receptor α_(2A), α_(2B), α_(1B)and α_(1D) may be assessed by methods known in the art, such as standardα_(2A), α_(2B), α_(1B) and α_(1D) receptor cell membrane-based or intactcell-based activity assays. For example, the Aequorin-based assay may beused to assess antagonist activity to the adrenergic receptor α_(2A),α_(2B), α_(1B) or α_(1D) and the cell membrane-based GTPγS binding assaymay be used to assess antagonist activity to the adrenergic receptorα_(2B).

In one variation, adrenergic receptor α_(2A) antagonists as providedherein exhibit an IC₅₀ value equal to or less than about any one of 100nM, 30 nM or 10 nM at a given concentration of agonist (e.g.concentration corresponding to EC₈₀ of UK14304 (for Aequorin assay) inan adrenergic receptor α_(2A) antagonist assay.

In another variation, a compound provided herein binds to and is anantagonist of the adrenergic receptor α_(2A), wherein the compound isalso an antagonist of the adrenergic receptor α_(2B) and exhibits anIC₅₀ value that is equal to or less than about any one of 100 nM, 30 nMor 10 nM at a given concentration of agonist (e.g. concentrationcorresponding to EC₈₀ of oxymetazoline (for Aequorin assay) orguanfacine (for GTPγS assay) in an adrenergic receptor α_(2B) antagonistassay. In some embodiments, adrenergic receptor α_(2A) antagonists asprovided herein exhibit: (i) an IC₅₀ value in an α_(2A) antagonist assayequal to or less than about any one of 100 nM, 30 nM or 10 nM at a givenconcentration of agonist (e.g. concentration corresponding to EC₈₀ ofUK14304 (for Aequorin assay), and (ii) an IC₅₀ value in an α_(2B)antagonist assay that is equal to or less than about any one of 100 nM,30 nM or 10 nM at a given concentration of agonist (e.g. concentrationcorresponding to EC₈₀ of oxymetazoline (for Aequorin assay) orguanfacine (for GTPγS assay). In another variation, a compound providedherein binds to and is an antagonist of the adrenergic receptor α_(2A),wherein the compound is also an antagonist of the adrenergic receptorα_(1B) and exhibits an IC₅₀ value that is equal to or less than aboutany one of 100 nM, 30 nM or 10 nM at a given concentration of agonist(e.g. concentration corresponding to EC₈₀ of cirazoline (for Aequorinassay) in an adrenergic receptor α_(1B) antagonist assay. In someembodiments, adrenergic receptor α_(2A) antagonists as provided hereinexhibit: (i) an IC₅₀ value equal to or less than about any one of 100nM, 30 nM or nM at a given concentration of agonist (e.g. concentrationcorresponding to EC₈₀ of UK14304 (for Aequorin assay) in an adrenergicreceptor α_(2A) antagonist assay, and (ii) an IC₅₀ value equal or lessthan about any one of 100 nM or 30 nM or 10 nM at a given concentrationof agonist (e.g. concentration corresponding to EC₈₀ of cirazoline) inan adrenergic receptor α_(1B) antagonist assay. In yet anothervariation, a compound provided herein binds to and is an antagonist ofthe adrenergic receptor α_(2A), wherein the compound is also anantagonist of the adrenergic receptor α_(1D) and exhibits an IC₅₀ valuethat is equal to or less than about any one of 100 nM, 30 nM or 10 nM ata given concentration of agonist (e.g. concentration corresponding toEC₈₀ of cirazoline (for Aequorin assay) in an adrenergic receptor α_(1D)antagonist assay. In some embodiments, adrenergic receptor α_(2A)antagonists as provided herein exhibit: (i) an IC₅₀ value equal to orless than about any one of 100 nM, 30 nM or 10 nM at a givenconcentration of agonist (e.g. concentration corresponding to EC₈₀ ofUK14304 (for Aequorin assay) in an adrenergic receptor α_(2A) antagonistassay, and (ii) an IC₅₀ value equal or less than about any one of 100 nMor 30 nM or 10 nM at a given concentration of agonist (e.g.concentration corresponding to EC₈₀ of cirazoline) in an adrenergicreceptor α_(1D) antagonist assay.

In yet another embodiment, adrenergic receptor α_(2A) antagonists asprovided herein exhibit: (i) an IC₅₀ value in an α_(2A) antagonist assayequal to or less than about any one of 100 nM, 30 nM or nM at a givenconcentration of agonist (e.g. concentration corresponding to EC₈₀ ofUK14304 (for Aequorin assay); (ii) an IC₅₀ value in an α_(2B) antagonistassay that is equal to or less than about any one of 100 nM, 30 nM or 10nM at a given concentration of agonist (e.g. concentration correspondingto EC₈₀ of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγSassay); and (iii) an IC₅₀ value equal or less than about any one of 100nM, 30 nM or 10 nM at a given concentration of agonist (e.g.concentration corresponding to EC₈₀ of cirazoline) in an adrenergicreceptor α_(1B) antagonist assay. In another embodiment, adrenergicreceptor α_(2A) antagonists as provided herein exhibit: (i) an IC₅₀value in an α_(2A) antagonist assay equal to or less than about any oneof 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g.concentration corresponding to EC₈₀ of UK14304 (for Aequorin assay);(ii) an IC₅₀ value in an α_(2B) antagonist assay that is equal to orless than about any one of 100 nM, 30 nM or 10 nM at a givenconcentration of agonist (e.g. concentration corresponding to EC₈₀ ofoxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay); and(iii) an IC₅₀ value equal or less than about any one of 100 nM, 30 nM or10 nM at a given concentration of agonist (e.g. concentrationcorresponding to EC₈₀ of cirazoline) in an adrenergic receptor α_(1D)antagonist assay. In another embodiment, adrenergic receptor α_(2A)antagonists as provided herein exhibit: (i) an IC₅₀ value in an α_(2A)antagonist assay equal to or less than about any one of 100 nM, 30 nM or10 nM at a given concentration of agonist (e.g. concentrationcorresponding to EC₈₀ of UK14304 (for Aequorin assay); (ii) an IC₅₀value equal or less than about any one of 100 nM, 30 nM or 10 nM at agiven concentration of agonist (e.g. concentration corresponding to EC₈₀of cirazoline) in an adrenergic receptor α_(1B) antagonist assay; and(iii) an IC₅₀ value equal or less than about any one of 100 nM, 30 nM or10 nM at a given concentration of agonist (e.g. concentrationcorresponding to EC₈₀ of cirazoline) in an adrenergic receptor α_(1D)antagonist assay.

In yet another embodiment, adrenergic receptor α_(2A) antagonists asprovided herein exhibit: (i) an IC₅₀ value in an α_(2A) antagonist assayequal to or less than about any one of 100 nM, 30 nM or nM at a givenconcentration of agonist (e.g. concentration corresponding to EC₈₀ ofUK14304 (for Aequorin assay); (ii) an IC₅₀ value in an α_(2B) antagonistassay that is equal to or less than about any one of 100 nM, 30 nM or 10nM at a given concentration of agonist (e.g. concentration correspondingto EC₈₀ of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγSassay); (iii) an IC₅₀ value equal or less than about any one of 100 nM,30 nM or 10 nM at a given concentration of agonist (e.g. concentrationcorresponding to EC₈₀ of cirazoline) in an adrenergic receptor α_(1B)antagonist assay; and (iv) an IC₅₀ value equal or less than about anyone of 100 nM, 30 nM or 10 nM at a given concentration of agonist (e.g.concentration corresponding to EC₈₀ of cirazoline) in an adrenergicreceptor α_(1D) antagonist assay.

In one variation, adrenergic receptor α_(2A) antagonists as providedherein exhibit an IC₅₀ value equal to or less than about any one of 100nM, 30 nM or 10 nM at a given concentration of agonist (e.g.concentration corresponding to EC₈₀ of UK14304 (for Aequorin assay) inan adrenergic receptor α_(2A) antagonist assay. In one variation,adrenergic receptor α_(2A) antagonists as provided herein exhibit anIC₅₀ value equal to or less than about 10 nM at a given concentration ofagonist (e.g. concentration corresponding to EC₈₀ of UK14304 (forAequorin assay) in an adrenergic receptor α_(2A) antagonist assay. Inone variation, adrenergic receptor α_(2A) antagonists as provided hereinexhibit an IC₅₀ value in an adrenergic receptor α_(2A) antagonist assayequal to or less than about any one of 100 nM, 30 nM or 10 nM at aconcentration of UK14304 (for Aequorin assay) corresponding to its EC₈₀concentration obtained by assay protocols described herein. In onevariation, adrenergic receptor α_(2A) antagonists as provided hereinexhibit an IC₅₀ value equal to or less than about any one of 100 nM, 30nM or 10 nM at a concentration of UK14304 between about 0.4 and about 40nM in an adrenergic receptor α_(2A) (Aequorin) antagonist assay. In onevariation, adrenergic receptor α_(2A) antagonists as provided hereinexhibit an IC₅₀ value equal to or less than about any one of 100 nM, 30nM or 10 nM at a concentration of about 4.57 nM UK14304 in an adrenergicreceptor α_(2A) (Aequorin) antagonist assay.

In one variation adrenergic receptor α_(2A) antagonists as providedherein exhibit an IC₅₀ value equal to or less than about any one of 100nM, 30 nM or 10 nM at a given concentration of agonist (e.g.concentration corresponding to EC₈₀ of oxymetazoline (for Aequorinassay) or guanfacine (for GTPγS assay) in an α_(2B) antagonist assay. Insome embodiments, adrenergic receptor α_(2A) antagonists as providedherein exhibit an IC₅₀ value equal to or less than about 10 nM at agiven concentration of agonist (e.g. concentration corresponding to EC₈₀of oxymetazoline (for Aequorin assay) or guanfacine (for GTPγS assay) inan α_(2B) antagonist assay. In some embodiments, a compound describedherein exhibits an IC₅₀ value in an α_(2B) antagonist assay equal to orless than about any one of 100 nM, 30 nM or 10 nM at a concentration ofoxymetazoline corresponding to its EC₈₀ concentration as obtained byassay protocols described herein. In some embodiments, a compounddescribed herein exhibits an IC₅₀ value in an α_(2B) antagonist(Aequorin) assay equal to or less than about any one of 100 nM, 30 nM or10 nM at a concentration of oxymetazoline between about 50 nM to about5000 nM. In some embodiments, a compound described herein exhibits anIC₅₀ value in an α_(2B) antagonist (Aequorin) assay equal to or lessthan about any one of 100 nM, 30 nM or 10 nM at a concentration of about480 nM oxymetazoline. In some embodiments, a compound described hereinexhibits an IC₅₀ value in an α_(2B) antagonist (GTPγS) assay equal to orless than about any one of 100 nM, 30 nM or 10 nM at a concentration ofguanfacine between about 50 nM to about 5000 nM. In some embodiments, acompound described herein exhibits an IC₅₀ value in an α_(2B) antagonistassay equal to or less than about any one of 100 nM, 30 nM or 10 nM at aconcentration of about 500 nM guanfacine, which is a particularvariation, is 504 nM guanfacine.

In one variation, a compound described herein exhibits an IC₅₀ value inan α_(1B) antagonist assay equal to or less than about any one of 100nM, 30 nM or 10 nM at a given concentration of agonist (e.g.concentration corresponding to EC₈₀ of cirazoline) in an adrenergicreceptor α_(1B) antagonist assay. In some embodiments, a compounddescribed herein exhibits an IC₅₀ value in an α_(1B) antagonist assayequal to or less than about 10 nM at a given concentration of agonist(e.g. concentration corresponding to EC₈₀ of cirazoline) in anadrenergic receptor α_(1B) antagonist assay. In some embodiments, acompound described herein exhibits an IC₅₀ value in an α_(1B) antagonistassay equal to or less than about any one of 100 nM, 30 nM or 10 nM at aconcentration of cirazoline corresponding to its EC₈₀ concentration asobtained by assay protocols described herein. In some embodiments, acompound described herein exhibits an IC₅₀ value in an α_(1B) antagonist(Aequorin) assay equal to or less than about any one of 100 nM, 30 nM or10 nM at a concentration of cirazoline between about 2.3 nM and about230 nM. In some embodiments, a compound described herein exhibits anIC₅₀ value in an α_(1B) antagonist (Aequorin) assay equal to or lessthan about any one of 100 nM, 30 nM or 10 nM at a concentration of about25 nM cirazoline, which in a particular variation is 23.56 nMcirazoline.

In one variation, a compound described herein exhibits an IC₅₀ value inan α_(1D) antagonist assay equal to or less than about any one of 100nM, 30 nM or 10 nM at a given concentration of agonist (e.g.concentration corresponding to EC₈₀ of cirazoline) in an adrenergicreceptor α_(1D) antagonist assay. In some embodiments, a compounddescribed herein exhibits an IC₅₀ value in an α_(1D) antagonist assayequal to or less than about 10 nM at a given concentration of agonist(e.g. concentration corresponding to EC₈₀ of cirazoline) in anadrenergic receptor α_(1D) antagonist assay. In some embodiments, acompound described herein exhibits an IC₅₀ value in an α_(1D) antagonistassay equal to or less than about any one of 100 nM, 30 nM or 10 nM at aconcentration of cirazoline corresponding to its EC₈₀ concentration asobtained by assay protocols described herein. In some embodiments, acompound described herein exhibits an IC₅₀ value in an α_(1D) antagonistassay equal to or less than about any one of 100 nM, 30 nM or 10 nM at aconcentration of cirazoline between about 2.3 nM and about 230 nM. Insome embodiments, a compound described herein exhibits an IC₅₀ value inan α_(1D) antagonist assay equal to or less than about any one of 100nM, 30 nM or 10 nM at a concentration of about 25 nM cirazoline, whichin a particular variation is 23.56 nM cirazoline.

In some embodiments, compounds provided herein exhibit inverse agonistactivity for the adrenergic receptor α_(2A). In some embodiments, thecompound binds to and is an inverse agonist of the adrenergic receptorα_(2A) and binds to and is antagonist of one or more of the adrenergicreceptors α_(2B), α_(1B) and α_(1D). In one variation, the compoundbinds to and is an inverse agonist of the adrenergic receptor α_(2A) andbinds to and is antagonist of any one of the adrenergic receptorsα_(2B), α_(1B) and α_(1D). In another variation, the compound binds toand is an inverse agonist of the adrenergic receptor α_(2A) and binds toand is antagonist of any two of the adrenergic receptors α_(2B), α_(1B)and α_(1D). In yet another variation, the compound binds to and is aninverse agonist of the adrenergic receptor α_(2A) and binds to and isantagonist of adrenergic receptors α_(2B), α_(1B) and α_(1D). Inverseagonist activity to the adrenergic receptor α_(2A) may be assessed bymethods known in the art, such as those described in Wade, S. M. et al.,Mol. Pharmacol. 59:532-542 (2001).

It is understood and clearly conveyed herein that any of the bindingprofiles detailed herein can be combined with any of the antagonistprofiles detailed herein, as if each and every combination were listedseparately. For example, in one variation, a compound provided hereinexhibits (i) greater than or equal to about any one of 50%, 55%, 60%,65%, 70%, 80%, 85%, 90%, 95%, or between about 50% and 90%, betweenabout 60% and about 90%, between about 70% and about 90%, or about 80%and about 100% inhibition of α_(2A) ligand binding at 0.1 μM toadrenergic receptor α_(2A) and an IC₅₀ value equal to or less than aboutany one of 100 nM, 30 nM or 10 nM at a given concentration of agonist(e.g. concentration corresponding to EC₈₀ of UK14304 (for Aequorinassay) in an adrenergic receptor α_(2A) antagonist assay; and (ii)greater than or equal to about any one of 50%, 55%, 60%, 65%, 70%, 80%,85%, 90%, 95%, or between about 50% and 90%, between about 60% and about90%, between about 70% and about 90%, or about 80% and about 100%inhibition of α_(2B) ligand binding at 0.1 μM to adrenergic receptorα_(2B) and IC₅₀ value equal to or less than about any one of 100 nM, 30nM or 10 nM at a given concentration of agonist (e.g. concentrationcorresponding to EC₈₀ of oxymetazoline (for Aequorin assay) orguanfacine (for GTPγS assay) in an α_(2B) antagonist assay.

Medical Use

Without being bound by theory, it is believed that compounds that bindto and are antagonists of the adrenergic receptor α_(2A) affect anincrease in insulin secretion and/or promote insulin release into theblood stream in an individual, which aids in glucose uptake. However,such compounds may also increase an individual's blood pressure. Whenthe adrenergic receptor α_(2A) antagonists as provided herein also bindto and are antagonists of the adrenergic receptor α_(2B) and/or theadrenergic receptor α_(1B), and/or the adrenergic receptor α_(1D), it isbelieved that the increases in an individual's blood pressure due toantagonizing the adrenergic receptor α_(2A) may be reduced oreliminated. If an adrenergic receptor α_(2A) antagonist as providedherein is not also an antagonist of the adrenergic receptor α_(2B)and/or the adrenergic receptor α_(1B) and/or the adrenergic receptorα_(1D), then the increase in an individual's blood pressure as a resultof the adrenergic receptor α_(2A) antagonist may be reduced oreliminated by administering the compound in conjunction with a secondagent that reduces, or is expected to reduce, blood pressure in anindividual.

Compounds provided herein, such as the adrenergic receptor α_(2A)antagonists provided herein, are expected to find use in therapy,particularly in indications in which an increase in an individual'sinsulin secretion and/or an increase in insulin release into the bloodstream would be, or would be expected to be, beneficial. Thus,individuals who have a disease or condition that involves reduced orimpaired insulin secretion and/or release may benefit from the compoundsdetailed herein, or pharmaceutically acceptable salts thereof. Suchindications include, but are not limited to type 2 diabetes, glucoseintolerance and metabolic syndrome. An individual who has a disease orcondition that involves reduced or impaired insulin secretion and/orrelease may experience one or more beneficial or desirable results uponadministration of an adrenergic receptor α_(2A) antagonist providedherein, or pharmaceutically acceptable salt thereof. In one aspect, thebeneficial or desirable result is a reduction in the individual's bloodglucose level for a period of time (e.g., about any one of 6, 12, 24 or48 hours or more) following administration of the compound orpharmaceutically acceptable salt thereof. In another aspect, thebeneficial or desirable result is an increase in glucose metabolism fora period of time (e.g., about any one of 6, 12, 24 or 48 hours or more)following administration of the compound or pharmaceutically acceptablesalt thereof.

Compounds that are inverse agonists of the adrenergic receptor α_(2A)may stimulate islet cell release of insulin even in the absence ofsympathetic stimulation of the adrenergic receptor α_(2A) withepinephrine and/or norepinephrine. Inverse agonists of the adrenergicreceptor α_(2A) provided herein are thus expected to find use intherapy, particularly in indications in which stimulation of islet cellrelease of insulin would be, or would be expected to be, beneficial.Individuals who have a disease or condition responsive to inhibition ofthe adrenergic receptor α_(2A) may benefit from the compounds detailedherein, or pharmaceutically acceptable salts thereof. Such indicationsinclude, but are not limited to type 2 diabetes, metabolic syndrome, andglucose intolerance.

In one aspect, compounds are provided that do not bind appreciably anyone or more of the histamine, dopamine and serotonin receptors. In anyof the methods detailed herein, in one variation the individual does nothave a cognitive disorder, psychotic disorder, neurotransmitter-mediateddisorder and/or neuronal disorder. As used herein, the term “cognitivedisorders” refers to and intends diseases and conditions that arebelieved to involve or be associated with or do involve or areassociated with progressive loss of structure and/or function ofneurons, including death of neurons, and where a central feature of thedisorder may be the impairment of cognition (e.g., memory, attention,perception and/or thinking). These disorders include pathogen-inducedcognitive dysfunction, e.g., HIV associated cognitive dysfunction andLyme disease associated cognitive dysfunction. Examples of cognitivedisorders include Alzheimer's Disease, Huntington's Disease, Parkinson'sDisease, schizophrenia, amyotrophic lateral sclerosis (ALS), autism,mild cognitive impairment (MCI), stroke, traumatic brain injury (TBI)and age-associated memory impairment (AAMI). As used herein, the term“psychotic disorders” refers to and intends mental diseases orconditions that are believed to cause or do cause abnormal thinking andperceptions. Psychotic disorders are characterized by a loss of realitywhich may be accompanied by delusions, hallucinations (perceptions in aconscious and awake state in the absence of external stimuli which havequalities of real perception, in that they are vivid, substantial, andlocated in external objective space), personality changes and/ordisorganized thinking. Other common symptoms include unusual or bizarrebehavior, as well as difficulty with social interaction and impairmentin carrying out the activities of daily living. Exemplary psychoticdisorders are schizophrenia, bipolar disorders, psychosis, anxiety anddepression. As used herein, the term “neurotransmitter-mediateddisorders” refers to and intends diseases or conditions that arebelieved to involve or be associated with or do involve or areassociated with abnormal levels of neurotransmitters such as histamine,serotonin, dopamine, norepinephrine or impaired function of aminergic Gprotein-coupled receptors. Exemplary neurotransmitter-mediated disordersinclude spinal cord injury, diabetic neuropathy, allergic diseases anddiseases involving geroprotective activity such as age-associated hairloss (alopecia), age-associated weight loss and age-associated visiondisturbances (cataracts). Abnormal neurotransmitter levels areassociated with a wide variety of diseases and conditions including, butnot limited, to Alzheimer's disease, Parkinson's Disease, autism,Guillain-Barré syndrome, mild cognitive impairment, schizophrenia,anxiety, multiple sclerosis, stroke, traumatic brain injury, spinal cordinjury, diabetic neuropathy, fibromyalgia, bipolar disorders, psychosis,depression and a variety of allergic diseases. As used herein, the term“neuronal disorders” refers to and intends diseases or conditions thatare believed to involve, or be associated with, or do involve or areassociated with neuronal cell death and/or impaired neuronal function ordecreased neuronal function. Exemplary neuronal indications includeneurodegenerative diseases and disorders such as Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson'sdisease, canine cognitive dysfunction syndrome (CCDS), Lewy bodydisease, Menkes disease, Wilson disease, Creutzfeldt-Jakob disease, Fahrdisease, an acute or chronic disorder involving cerebral circulation,such as ischemic or hemorrhagic stroke or other cerebral hemorrhagicinsult, age-associated memory impairment (AAMI), mild cognitiveimpairment (MCI), injury-related mild cognitive impairment (MCI),post-concussion syndrome, post-traumatic stress disorder, adjuvantchemotherapy, traumatic brain injury (TBI), neuronal death mediatedocular disorder, macular degeneration, age-related macular degeneration,autism, including autism spectrum disorder, Asperger syndrome, and Rettsyndrome, an avulsion injury, a spinal cord injury, myasthenia gravis,Guillain-Barré syndrome, multiple sclerosis, diabetic neuropathy,fibromyalgia, neuropathy associated with spinal cord injury,schizophrenia, bipolar disorder, psychosis, anxiety or depression.

The adrenergic receptor α_(2A) antagonists provided herein may also beadministered in combination with an insulin sensitizer, and as such finduse in therapy for treating indications in which increasing in anindividual's insulin secretion and/or insulin release into the bloodstream would be, or would be expected to be, beneficial, provided thatthe therapy also promotes insulin responsiveness to glucose. In oneaspect, where the adrenergic receptor α_(2A) antagonists provided hereinmay be administered in combination with another anti-diabetic drug, suchas an insulin sensitizer, the beneficial or desirable result of which isa reduction in the individual's blood glucose levels for a period oftime (e.g., about any one of 6, 12, 24 or 48 hours or more) followingadministration of the compound or pharmaceutically acceptable saltthereof. In a particular variation, such a therapy may include anadrenergic receptor α_(2A) antagonist provided herein and a second agentthat reduces, or is expected to reduce, blood pressure and an insulinsensitizer. In a further variation, such a therapy may include anadrenergic receptor α_(2A) antagonist provided herein and a second agentthat (i) is an agent that reduces, or is expected to reduce, bloodpressure; (ii) is an agent that is an insulin sensitizer or (iii) is anagent that induces no or reduced (in number and/or severity)hypoglycemic episodes.

Methods

Methods of using the compounds detailed herein, or pharmaceutical saltsthereof, to increase an individual's ability to secrete insulin and/orto release insulin into the blood stream are provided. In any of themethods detailed herein, the method may comprise the step ofadministering an adrenergic receptor α_(2A) antagonist, orpharmaceutically acceptable salt thereof, to an individual in needthereof. In one aspect, the adrenergic receptor α_(2A) antagonists ofthe methods also bind to and are antagonists of one or more of theadrenergic receptors α_(2B), α_(1B) and α_(1D). In one variation, amethod of increasing insulin secretion and/or release into the bloodstream in an individual in need thereof is provided, wherein the methodcomprises administering to an individual in need thereof a compound thatbinds to and is an antagonists of the adrenergic receptor α_(2A). Inanother variation, a method of increasing insulin secretion and/orrelease into the blood stream in an individual in need thereof isprovided, wherein the method comprises administering to an individual inneed thereof a compound that binds to and is an antagonists of theadrenergic receptor α_(2A), wherein the compound either (a) also bindsto and is an antagonist of the adrenergic receptor α_(2B) or (b) isadministered in conjunction with a second agent that reduces, or isexpected to reduce, blood pressure in the individual. In somevariations, methods of using the compounds detailed herein to increasean individual's ability to secrete insulin and/or release insulin intothe blood stream while reducing or eliminating an increase in theindividual's blood pressure due to antagonizing the adrenergic receptorα_(2A) are thus provided. Methods of using the compounds detailed hereinto promote an individual's ability to metabolize glucose while reducingor eliminating an increase in the individual's blood pressure due toantagonizing the adrenergic receptor α_(2A) are also provided. It isunderstood that in methods of promoting an individual's ability tometabolize glucose, the method in one variation may employadministration of both an adrenergic receptor α_(2A) antagonist and aninsulin sensitizer. The compounds or pharmaceutical salts thereof mayalso find use in treating a disease or condition that is, or is expectedto be, responsive to an increase in an individual's ability to secreteinsulin and/or release of insulin into the blood stream. Individuals tobe treated in such methods in one variation have a reduced or impairedability to secrete insulin and/or release insulin into the blood stream.The compounds as provided herein may also be used in a method ofdelaying the onset and/or development of a disease or conditionassociated with reduced or impaired ability to secrete insulin and/orrelease insulin into the blood stream, comprising administering acompound as provided herein, or a pharmaceutical salt thereof, to anindividual who is at risk of developing a disease or conditionassociated with reduced or impaired ability to secrete insulin and/orrelease insulin into the blood stream. The compounds as provided hereinmay also be used in a method of delaying the onset and/or development ofa disease or condition associated with reduced or impaired ability tometabolize glucose, comprising administering an adrenergic receptorα_(2A) antagonist as provided herein, or a pharmaceutical salt thereof,to an individual who is at risk of developing a disease or conditionassociated with reduced or impaired ability to metabolize glucose. Theindividual may be an adult, child or teen who has or is at risk ofdeveloping type 2 diabetes, glucose intolerance or metabolic syndrome.

Non-limiting examples of a second agent that lowers blood pressureincludes diuretics, angiotensin-converting enzyme (ACE) inhibitors,angiotensin-2 receptor antagonists, beta blockers, calcium channelblockers, or any combination thereof.

Also provided herein are methods of using an adrenergic receptor α_(2A)antagonist, or a pharmaceutically acceptable salt thereof, incombination with one or more of other anti-diabetic agents, such asinsulin sensitizers and secretagogue agents. Non-limiting examples ofanti-diabetic agents includes insulin therapies (e.g., insulin glargineand insulin lispro), secretagogue agents that increase insulin secretionand/or release (e.g., sulfonylureas such as glimepiride, glipizide andglyburide; meglitinides such as repaglinide and nateglinide), agentsthat increase insulin sensitivity (e.g., thiazolidinediones, such aspioglitazone and rosiglitazone), agents that decrease glucose absorption(e.g., alpha-glucosidase inhibitors such as miglitol and acarbose); andagents that reduce gluconeogenesis (biguanide such as metformin);amylinomimetics such as pramlintide, and agents that sequester bileacids.

Further provided herein are methods of using an adrenergic receptorα_(2A) antagonist, or a pharmaceutically acceptable salt thereof, incombination with an insulin sensitizer to promote insulin responsivenessand increase an individual's ability to secrete insulin and/or torelease insulin into the blood stream. In one aspect, the adrenergicreceptor α_(2A) antagonist also binds to and is an antagonist of one ormore of the adrenergic receptors α_(2B), α_(1B) and α_(1D). In onevariation, a method of promoting insulin responsiveness and increasinginsulin secretion and/or release into the blood stream in an individualin need thereof is provided, wherein the method comprises administeringto an individual in need thereof an insulin sensitizer and an adrenergicreceptor α_(2A) antagonist. In another variation, a method of promotinginsulin responsiveness and increasing insulin secretion and/or releaseinto the blood stream in an individual in need thereof is provided,wherein the method comprises administering to an individual in needthereof an insulin sensitizer and a compound that binds to and is anantagonists of the adrenergic receptor α_(2A), wherein the compoundeither (a) also binds to and is an antagonist of the adrenergic receptorα_(2B) or (b) is administered in conjunction with a second agent thatreduces, or is expected to reduce, blood pressure in the individual. Ina particular variation, a method of promoting insulin responsiveness andincreasing insulin secretion and/or release into the blood stream in anindividual in need thereof is provided, wherein the method comprisesadministering to an individual in need thereof an insulin sensitizer andan adrenergic receptor α_(2A) antagonist that also binds to and is anantagonist of one or more of the adrenergic receptors α_(2B), α_(1B) andα_(1D). In some embodiments, the method comprises administering any ofthe compounds detailed herein in combination with an insulin sensitizer.

In one aspect, a method of treating type 2 diabetes is provided, wherethe method comprises administering to an individual in need thereof acompound detailed herein, such as an adrenergic receptor α_(2A)antagonist detailed herein. In one aspect, the compound binds to and isan adrenergic receptor α_(2A) antagonist. In some embodiments, theadrenergic receptor α_(2A) antagonist also binds to and is an antagonistof one or more of the adrenergic receptors α_(2B), α_(1B) and α_(1D). Inanother aspect, a method of treating type 2 diabetes is provided, wherethe method comprises administering to an individual in need thereof acompound as provided herein, wherein the compound binds to and is anantagonist of the adrenergic receptor α_(2A) and wherein the compoundeither (a) also binds to and is an antagonist of the adrenergic receptorα_(2B) or (b) is administered in conjunction with a second agent thatreduces, or is expected to reduce, blood pressure in an individual.Individuals to be treated in such methods in one variation have type 2diabetes. The compounds as provided herein may also be used in a methodof delaying the onset and/or development of type 2 diabetes, comprisingadministering an adrenergic receptor α_(2A) antagonist, orpharmaceutically acceptable salt thereof, to an individual who has oneor more risk factors associated with developing type 2 diabetes. In onevariation, the compounds as provided herein are used in a method ofdelaying the onset and/or development of type 2 diabetes; and inducingextra-pancreatic effects such as reducing hepatic glucose production viaglycogenolysis or gluconegogenesis or both, comprising administering anadrenergic receptor α_(2A) antagonist, or pharmaceutically acceptablesalt thereof, to an individual such as an individual who has one or morerisk factors associated with developing type 2 diabetes. In onevariation, compounds provided herein may (i) have an extra-pancreaticeffect and/or (ii) prevent or lower hepatic glucose production.

Risk factors may include gender, race, ethnicity, age, family history,weight and/or lifestyle. For example, certain races and ethnicities(e.g., Blacks, Hispanics, Native Americans and Asians (which as usedherein includes individuals of the continent of Asia, such as Indiansand Chinese) and individuals of such descent) are more likely to developtype 2 diabetes. Being overweight (e.g., having a body mass index>25) isalso a risk factor for type 2 diabetes, with higher amount of fattytissue also correlating with higher resistance of cells to insulin.Inactivity, which can lead to weight gain, is also a risk factor fortype 2 diabetes (physical activity helps not only to control anindividual's weight, but also utilizes glucose as energy and makes cellsmore sensitive to insulin). Family history is often a risk factor formany diseases, including type 2 diabetes, where the risk of developingtype 2 diabetes increases if a parent or sibling has type 2 diabetes.The risk of developing type 2 diabetes also increases with age,especially after age 45, which may also correlate with a tendency toexercise less, lose muscle mass and gain weight with age. However, asobesity rates rise in children and young adults, type 2 diabetes isincreasing common in these individuals and children and young adults whoare overweight and/or sedentary are also at risk of developing type 2diabetes. Being pre-diabetic, in which an individual's blood sugar levelis higher than normal, but not high enough to be classified as type 2diabetes, if left untreated, often progresses to type 2 diabetes. Otherrisk factors associated with type 2 diabetes include: a woman who hashad gestational diabetes, gave birth to a baby weighing more than 9pounds or has a history of polycystic ovary disease (PCOS); anindividual who has metabolic syndrome; an individual who hashypertension; an individual who has a high-density lipoprotein (HDL)value under 35 mg/dL (milligrams per deciliter) and/or a triglyceridelevel over 250 mg/dL; and an individual with a history of vasculardisease, such as stroke. Individuals who have more than one risk factorare particularly susceptible to developing type 2 diabetes.

In one aspect, a method of treating glucose intolerance is provided,where the method comprises administering to an individual in needthereof an adrenergic receptor α_(2A) antagonist, or pharmaceuticallyacceptable salt thereof. In one aspect, the adrenergic receptor α_(2A)antagonist also binds to and is an antagonist of one or more of theadrenergic receptors α_(2B), α_(1B) and α_(1D). In another aspect, amethod of treating glucose intolerance is provided, where the methodcomprises administering to an individual in need thereof a compound asprovided herein, wherein the compound binds to and is an antagonist ofthe adrenergic receptor α_(2A) and wherein the compound either (a) alsobinds to and is an antagonist of the adrenergic receptor α_(2B) or (b)is administered in conjunction with a second agent that reduces, or isexpected to reduce, blood pressure in the individual. The compounds asprovided herein may also be used in a method of delaying the onsetand/or development of glucose intolerance, comprising administering acompound as provided herein to an individual who has one or more riskfactors associated with developing glucose intolerance. A method ofreducing blood glucose levels in an individual in need thereof is alsoprovided, the method comprising administering an adrenergic receptorα_(2A) antagonist, or pharmaceutically acceptable salt thereof, to theindividual. A method of enhancing glucose metabolism in an individual inneed thereof is also provided, the method comprising administering anadrenergic receptor α_(2A) antagonist, or pharmaceutically acceptablesalt thereof, to the individual.

Further provided are methods of using the compounds detailed herein, orpharmaceutical salts thereof, to regulate blood glucose levels in anindividual, for example, an individual experiencing hyperglycemia and/orundesirable fluctuation in blood glucose levels. In some embodiments,provided is a method of regulating blood glucose levels in an individualin need thereof, where the method comprises administering to anindividual in need thereof an adrenergic receptor α_(2A) antagonist. Insome embodiments, administration of an adrenergic receptor α_(2A)antagonist reduces the blood glucose levels in an individual (e.g., ahyperglycemic individual). In some embodiments, administration of anadrenergic receptor α_(2A) antagonist stabilizes the blood glucoselevels in an individual (e.g., an individual experiencing undesirablefluctuations in blood glucose levels). In some embodiments,administration of an adrenergic receptor α_(2A) antagonist reduces andstabilizes the blood glucose levels in an individual. In one aspect, theadrenergic receptor α_(2A) antagonist also binds to and is an antagonistof one or more of the adrenergic receptors α_(2B), α_(1B) and α_(1D). Inanother aspect, provided is a method of regulating (e.g., reducingand/or stabilizing) blood glucose levels in an individual in needthereof, where the method comprises administering to an individual inneed thereof a compound as provided herein, wherein the compound bindsto and is an antagonist of the adrenergic receptor α_(2A) and whereinthe compound either (a) also binds to and is an antagonist of theadrenergic receptor α_(2B) or (b) is administered in conjunction with asecond agent that reduces, or is expected to reduce, blood pressure inan individual. In some embodiments, the adrenergic receptor α_(2A)antagonist described herein may also be an inverse agonist of theadrenergic receptor α_(2A).

In some embodiments, provided is a method of reducing blood glucoselevel in an individual in need thereof, comprises administering to anindividual in need thereof an adrenergic receptor α_(2A) antagonist,wherein the blood glucose level is reduced to a desirable level. Theadrenergic receptor α_(2A) antagonist may be administered alone or incombination with other agents such as an agent that reduces bloodpressure in the individual. In some embodiments, the blood glucose levelis reduced by about 10%, about 20%, about 30%, about 40%, about 50%,about 60%, or about 70%, provided that the reduction in glucose leveldoes not result in hypoglycemia. In some embodiments, the blood glucoselevel is reduced by at least about 10%, at least about 20%, at leastabout 30%, at least about 40%, at least about 50%, or at least about60%, provided that the reduction in glucose level does not result inhypoglycemia. In some embodiments, the blood glucose level is reduced byless than about 10%, between about 10% and about 30%, between about 30%and about 50%, between about 10% and about 50%, between about 50% andabout 70%, between about 30% and about 70%, between about 20% and about40%, between about 40% and about 60%, or between about 20% and about60%, provided that the reduction in glucose level does not result inhypoglycemia. The reduction of blood glucose level occurs over a periodof time after administration of the adrenergic receptor α_(2A)antagonist. In some embodiments, the reduction of blood glucose occurswithin about 15 minutes after administration of the compound orpharmaceutically acceptable salt thereof. In some embodiments, thereduction of blood glucose occurs within about 30 minutes, within about1 hour, or within about 2 hours after administration of the adrenergicreceptor α_(2A) antagonist. In some embodiments, the reduction of bloodglucose occurs at about 15 minutes or more, at about 30 minutes or more,at about 1 hour or more, or at about 2 hours or more afteradministration of the adrenergic receptor α_(2A) antagonist. In someembodiments, the method results in a reduction in the individual's bloodglucose level by any of the amount described herein for a period of time(e.g., about any one of 0.5, 1, 2, 3, 6, 12, 24 or 48 hours or more)following administration of the compound or pharmaceutically acceptablesalt thereof. In some embodiments, the method results in a reduction inthe individual's blood glucose level by any of the amount describedherein for a period of about 1 hour, about 2 hours, about 3 hours, about6 hours, about 12 hours, or about 24 hours or more followingadministration of the compound or pharmaceutically acceptable saltthereof.

The blood glucose levels in an individual can be measured by methodsknown in the art, such as by a calorimetric method or by using a device(e.g., a glucose meter). A blood glucose level in the range of about 80to 120 mg/dL pre-meal and about 100 to 140 mg/dL post-meal is considereddesirable in healthy human beings. A blood glucose level at above thedesirable level is considered hyperglycemic, such as that in diabeticpatients. The blood glucose level in a mildly diabetic human is about100 to 200 mg/dL. The blood glucose level in a moderately diabetic humanis about 200 to 350 mg/dL. The blood glucose level in a severelydiabetic human is above 400 mg/dL. A blood glucose level at below thedesirable level is considered hypoglycemic, e.g., at below 60 to 80mg/dL. The blood glucose levels may be measured at a single time point.However, a more accurate measurement requires an average over multipletime points or an area under the curve (AUC) over a period of time(e.g., 2 to 3 hours). The blood glucose level over a past period ofabout 2-3 months may be established by measuring the glycosylatedhemoglobin (HbA1c) level in the blood. HbA1c is a useful way to monitora patient's overall response to diabetes treatment over time. The HbA1cin a healthy human being is about 5%. It is desirable for a diabeticpatient to keep the HbA1c level below about 7%. Provided is a method ofreducing blood glucose level in an individual having an Hb1Ac level ofabove about 7%, comprises administering to the individual an adrenergicreceptor α_(2A) antagonist, wherein the Hb1Ac level is reduced to belowabout 7% following administration of the compound or pharmaceuticallyacceptable salt thereof. In some embodiments, the adrenergic receptorα_(2A) antagonist also binds to and is an antagonist of one or more ofthe adrenergic receptors α_(2B), α_(1B) and α_(1D).

In one aspect, a method of treating metabolic syndrome is provided,where the method comprises administering to an individual in needthereof a compound detailed herein, such as an adrenergic receptorα_(2A) antagonist detailed herein. In one aspect, the compound binds toand is an adrenergic receptor α_(2A) antagonist. In some embodiments,the adrenergic receptor α_(2A) antagonist also binds to and is anantagonist of one or more of the adrenergic receptors α_(2B), α_(1B) andα_(1D). In another aspect, a method of treating metabolic syndrome isprovided, where the method comprises administering to an individual inneed thereof a compound as provided herein, wherein the compound bindsto and is an antagonist of the adrenergic receptor α_(2A), and whereinthe compound either (a) also binds to and is an antagonist of theadrenergic receptor α_(2B) or (b) is administered in conjunction with asecond agent that reduces, or is expected to reduce, blood pressure inan individual. The compounds as provided herein may also be used in amethod of delaying the onset and/or development of metabolic syndrome,comprising administering a compound as provided herein to an individualwho has one or more risk factors associated with developing metabolicsyndrome. In a particular variation of the methods relating to metabolicsyndrome, the adrenergic receptor α_(2A) antagonist is administered toan individual in conjunction with an insulin sensitizer.

As is understood by those of skill in the art, metabolic syndrome is acluster of conditions, which may include increased blood pressure,excess body fat around the waist, abnormal cholesterol levels andelevated insulin levels due to insulin resistance whereby cells have adiminished ability to respond to insulin and the pancreas compensates bysecreting more insulin leading to high insulin levels in blood.According to the American Heart Association and the National Heart,Lung, and Blood Institute, metabolic syndrome is present if anindividual has three or more of the following signs: blood pressureequal to or higher than 130/85 mm Hg; fasting blood sugar (glucose)equal to or higher than 100 mg/dL; large waist circumference, which formen is 40 inches or more and for women is 35 inches or more; low HDLcholesterol, which for men is under 40 mg/dL and for women is under 50mg/dL; and triglycerides equal to or higher than 150 mg/dL.

Treatment of metabolic syndrome requires a careful and well-balancedapproach to account for both treatment of elevated insulin levels andhigh blood pressure. Thus, it is desirable in the context of treatingmetabolic syndrome that a compound that is an antagonist of theadrenergic receptor α_(2A) is also an antagonist of the adrenergicreceptor α_(2B) and/or α_(1B) and/or α_(1D) to reduce blood pressure.Alternatively, an adrenergic receptor α_(2A) antagonist that does notalso antagonize the adrenergic receptor α_(2B) and/or α_(1B) may beadministered in conjunction with a second agent that reduces, or isexpected to reduce blood pressure in an individual. In one aspect,provided is a method of regulating (e.g., reducing and/or stabilizing)blood glucose levels and reducing the blood pressure in an individual inneed thereof (e.g., an individual experiencing metabolic syndrome, or anindividual with hypertension who is also suffering from obesity and/ortype 2 diabetes), where the method comprises administering to anindividual in need thereof an adrenergic receptor α_(2A) antagonist. Inone aspect, the adrenergic receptor α_(2A) antagonist also binds to andis an antagonist of one or more of the adrenergic receptors α_(2B),α_(1B) and α_(1D). In another aspect, provided a method of regulating(e.g., reducing and/or stabilizing) blood glucose levels and reducingthe blood pressure in an individual in need thereof, where the methodcomprises administering to an individual in need thereof a compound asprovided herein, wherein the compound binds to and is an antagonist ofthe adrenergic receptor α_(2A), and wherein the compound either (a) alsobinds to and is an antagonist of the adrenergic receptor α_(2B) or (b)is administered in conjunction with a second agent that reduces, or isexpected to reduce, blood pressure in an individual. In someembodiments, the compound is an antagonist and an inverse agonist of theadrenergic receptor α_(2A).

Risk factors associated with developing metabolic syndrome include: morethan one parent or sibling who has type 2 diabetes, individuals withhigh blood pressure and/or cardiovascular disease; individuals who areobese or overweight (e.g., individual's having a body mass index above25); individuals who have more fat around their waist than around theirhips (an apple shape); age greater than 40 years (although it isunderstood that children and young adults, particularly those who areoverweight and/or sedentary, may also be at risk for developingmetabolic syndrome); a woman who had gestational diabetes when pregnantor who has a history of polycystic ovary syndrome (PCOS); individualswho are pre-diabetic and individuals of Latino, Black, Asian or NativeAmerican ethnicity.

Further provided herein are methods of determining if an individualsuffering from glucose intolerance (e.g., an individual testing negativein a glucose tolerance test) has (i) reduced or impaired insulinsecretion or (ii) has reduced or impaired responsiveness to insulin, themethod comprising administering a compound provided herein to theindividual and testing the individual in a glucose tolerance test,wherein an increase in insulin levels after glucose challenge (theglucose tolerance test) indicates that the individual has reduced orimpaired insulin secretion; or wherein insufficient increases in insulinlevels indicates that the individual has reduced or impairedresponsiveness to insulin.

Provided herein are methods of assessing whether an individual is likelyto be responsive to a compound that promotes an increase in insulinsecretion and/or release (e.g., an adrenergic receptor α_(2A)antagonist, or pharmaceutically acceptable salt thereof), administeredeither alone or in conjunction with an insulin sensitizer. In one aspectof such a method, an individual who has failed a glucose tolerance test(e.g., an individual whose glucose levels do not return to normal levelsfollowing glucose challenge and/or whose insulin levels are notsufficiently elevated in response to administration of glucose, asmeasured by methods and as assessed by standards known in the art), isadministered glucose following administration of an adrenergic receptorα_(2A) antagonist, or pharmaceutically acceptable salt thereof, andtheir insulin levels are then assessed. In one embodiment of suchmethods, the adrenergic receptor α_(2A) antagonist is administered tothe individual about any one of 5, 10, 15, 30 and 60 minutes or more orbetween about 5 and about 15 or between about 5 and about 30 or betweenabout 5 and about 60 or between about 15 and about 30 or between about30 and about 60 minutes prior to administration of glucose. If such anindividual, after administration of glucose and an adrenergic receptorα_(2A) antagonist, or pharmaceutically acceptable salt thereof, exhibitsan increase in insulin levels, the individual may be an individual whois responsive to a compound that promotes an increase in insulinsecretion and/or release (e.g., an adrenergic receptor α_(2A)antagonist, or pharmaceutically acceptable salt thereof). If such anindividual exhibits an increase in insulin levels, but the individual'sglucose levels do not decrease, then the individual may be an individualwho is responsive to a compound that can increase insulin secretionand/or release (including but not limited to an adrenergic receptorα_(2A) antagonist, or pharmaceutically acceptable salt thereof), used inconjunction with an insulin sensitizer. Sufficient levels of insulinincrease and/or glucose decrease are known by those of skill in the art.Thus, a method of assessing whether an individual suffering from glucoseintolerance (e.g., an individual who has failed (e.g., within the last 6months, 3 months, 1 month, 2 weeks or 1 week) a glucose tolerance testadministered in the absence of an adrenergic receptor α_(2A) antagonist)is more likely to be responsive or less likely to be responsive to atherapy that can increase insulin secretion and/or release (includingbut not limited to an adrenergic receptor α_(2A) antagonist, orpharmaceutically acceptable salt thereof), is provided, the methodcomprising administering an adrenergic receptor α_(2A) antagonist, orpharmaceutically acceptable salt thereof, to the individual and testingthe individual in a glucose tolerance test, wherein an increase ininsulin levels after glucose challenge (the glucose tolerance test)indicates that the individual is more likely to be responsive to saidtherapy, and wherein a reduced or insignificant or no increase ininsulin levels indicates that the individual is less likely to beresponsive to said therapy.

Also provided herein are methods of selecting an individual sufferingfrom glucose intolerance (e.g., an individual who has failed a glucosetolerance test) for a therapy comprising a compound which increasesinsulin secretion and/or release (e.g. an adrenergic receptor α_(2A)antagonist) based on the levels of insulin and/or glucose of theindividual following a glucose tolerance test in which the individual isadministered an adrenergic receptor α_(2A) antagonist prior to glucosechallenge, wherein an increase in insulin levels after glucose challengeand/or failure of the individual's glucose levels to return to normalselects the individual for said therapy. Thus, a method of selecting anindividual for therapy comprising a compound that increases insulinsecretion and/or release is provided (e.g., an adrenergic receptorα_(2A) antagonist), the method comprising the steps of (i) administeringan adrenergic receptor α_(2A) antagonist to an individual who has failed(e.g., within the last 6 months, 3 months, 1 month, 2 weeks or 1 week) aglucose tolerance test administered in the absence of an adrenergicreceptor α_(2A) antagonist; (2) administering a glucose tolerance testin which glucose is administered after the administration of theadrenergic receptor α_(2A) antagonist; and (3) correlating the resultsof the glucose tolerance test administered in conjunction with theadministration of the adrenergic receptor α_(2A) antagonist to theindividual (e.g., where glucose is administered about any one of 5, 15,30, 60 or more minutes following administration of the adrenergicreceptor α_(2A) antagonist) with whether the individual is more or lesslikely to be responsive to an adrenergic receptor α_(2A) antagonist,either alone, or in conjunction with an insulin sensitizer; and (4)selecting an individual who is more likely to be responsive to acompound that increases insulin secretion and/or release (e.g., anadrenergic receptor α_(2A) antagonist for adrenergic receptor α_(2A)antagonist therapy). An individual so selected may then be administereda compound that increases insulin secretion and/or release (e.g., anadrenergic receptor α_(2A) antagonist for adrenergic receptor α_(2A)antagonist therapy). In one aspect, the individual is selected fortherapy if their insulin levels increase in response to the glucosetolerance test administered in conjunction with the administration ofthe adrenergic receptor α_(2A) antagonist. If such an individual alsoexhibits a normal reduction in glucose levels, the individual may beselected for monotherapy with a compound that increases insulinsecretion and/or release (e.g., an adrenergic receptor α_(2A)antagonist). However, if such an individual does not exhibit a normalreduction in glucose levels, the individual may be selected for therapywith a compound that increases insulin secretion and/or release (e.g.,an adrenergic receptor α_(2A) antagonist) in conjunction with an insulinsensitizer. Individuals so selected may then be administered a compoundthat increases insulin secretion and/or release (e.g., an adrenergicreceptor α_(2A) antagonist), either alone or in conjunction with aninsulin sensitizer. Methods of monitoring the treatment of an individualfor glucose intolerance are also provided.

Also provided herein are methods of treating an individual sufferingfrom a disease or condition which is, or is expected to be, responsiveto an increase in insulin secretion and/or release, the methodcomprising (i) determining insulin levels of an individual in a glucosetolerance test after administration of an adrenergic receptor α_(2A)antagonist and (ii) administering a compound that increases insulinsecretion and/or release (e.g., an adrenergic receptor α_(2A)antagonist) to an individual having an increase in insulin levels afterthe glucose tolerance test. In one aspect of such a method, theindividual has failed (e.g., recently failed) a glucose tolerance testadministered in the absence of an adrenergic receptor α_(2A) antagonistand the individual's insulin levels increase in response to a glucosetolerance test which employed administration of glucose and anadrenergic receptor α_(2A) antagonist.

In any of the methods employing a glucose tolerance test in conjunctionwith an adrenergic receptor α_(2A) antagonist, in one variation, if theindividual's insulin does not increase in response to a glucosechallenge in conjunction with an adrenergic receptor α_(2A) antagonist,the individual may have type 2 diabetes with a defect in insulinsecretion. Therefore, also provided are methods of identifyingindividuals who may have type 2 diabetes with a defect in insulinsecretion.

Some genetic polymorphisms of the adrenergic receptor α_(2A) geneassociate with high blood glucose and can be used to screen for patientswho respond to an adrenergic receptor α_(2A) antagonist with an increasein insulin secretion and a decrease in blood glucose. For example theDNA polymorphism Rs553668 located in the 3′ UTR region of adrenergicreceptor α_(2A) associates with overexpression of the adrenergicreceptor α_(2A), reduced insulin secretion, and increased type 2diabetes risk (Rosengren et al., Science 327:217 (2010) and Talmud etal., Diabetologia 54:1710 (2011)). Human pancreatic islets from Rs553668allele carriers exhibited reduced granule docking and secreted lessinsulin in response to glucose. Individuals with elevated blood glucosewould be screened for the polymorphism. Individuals heterozygous orhomozygous for this polymorphism would be anticipated to respond totreatment with an adrenergic receptor α_(2A) antagonist. Other DNApolymorphisms may also be used to identify individuals with elevatedblood sugar that would respond to an adrenergic receptor α_(2A)antagonist; for example Rs7911129, Rs1971596, Rs602618, and Rs2203616.Thus provided herein is a method of selecting an individual for therapycomprising a compound that (i) increases insulin secretion and/orrelease, and/or (ii) regulates blood glucose (e.g., an adrenergicreceptor α_(2A) antagonist), the method comprising screening theindividual for polymorphisms of the adrenergic receptor α_(2A) geneassociate with high blood glucose, such as one or more of the DNApolymorphisms Rs553668, Rs7911129, Rs1971596, Rs602618 and Rs2203616.

Also provided is a method of regulating (e.g., reducing and/orstabilizing) blood glucose levels in an individual, the method comprisesthe steps of (i) screening the individual for genetic polymorphisms ofthe adrenergic receptor α_(2A) gene associate with high blood glucose;and (ii) administering to the individual carrying one or more geneticpolymorphisms of the adrenergic receptor α_(2A) gene associated withhigh blood glucose an adrenergic receptor α_(2A) antagonist. In onevariation, provided is a method of increasing insulin secretion and/orrelease into the blood stream in an individual, the method comprises thesteps of (i) screening the individual for genetic polymorphisms of theadrenergic receptor α_(2A) gene associate with high blood glucose; and(ii) administering to the individual carrying one or more geneticpolymorphisms of the adrenergic receptor α_(2A) gene associated withhigh blood glucose an adrenergic receptor α_(2A) antagonist. Furtherprovided are methods of treating type 2 diabetes, glucose intoleranceand/or metabolic syndrome, where the method comprises administering toan individual in need thereof an adrenergic receptor α_(2A) antagonist,wherein the individual carries one or more genetic polymorphisms of theadrenergic receptor α_(2A) gene associated with high blood glucose, suchas one or more of the DNA polymorphisms Rs553668, Rs7911129, Rs1971596,Rs602618 and Rs2203616. In some embodiments, the adrenergic receptorα_(2A) antagonist also binds to and is an antagonist of one or more ofthe adrenergic receptors α_(2B), α_(1B) and α_(1D). In some embodiments,the adrenergic receptor α_(2A) antagonist also binds to and is anantagonist of the adrenergic receptors α_(2B). In some embodiments, themethod of regulating blood glucose levels, increasing insulin secretionand/or release into the blood stream, or treating type 2 diabetes,glucose intolerance and/or metabolic syndrome, further comprisesadministering to the individual a second agent that reduces, or isexpected to reduce, blood pressure in an individual.

Compounds described herein showing adrenergic receptors α_(2A) andadrenergic receptor α_(2B) antagonist activity may find particular usein patients with fatty liver or/and obesity or/and hypertension withtype-2 diabetes associated with glucose intolerance; and super-addedwith polymorphisms in the adrenergic receptor α_(2A) gene.

Cell Viability and Mitochondrial Health

Methods of promoting cellular viability by promoting mitochondrialhealth are provided, the methods comprising contacting the cell with acompound detailed herein. The methods are applicable to various cells,such as neuronal and non-neuronal cells. In one variation, the cell is anon-neuronal cell, such as a renal or cardiac cell (e.g., myocardialmuscle cell). In one aspect, methods of promoting cellular viability areprovided wherein the cell is one whose viability would be, or would beexpected to be, promoted by nutrient influx and/or oxygenation. Methodsof promoting cellular viability in a cell experiencing, or exhibitingsymptoms of, mitochondrial stress are also provided.

Methods of treating a disease or condition that is, or is expected tobe, responsive to promoting mitochondrial health and cell viability arealso described, the methods comprising administering to an individual inneed thereof an effective amount of a compound provided herein. In onevariation, the disease or condition is one which is associated withdysfunction of mitochondria in a non-neuronal cell. In a particularvariation, the disease or condition is one which is associated withdysfunction of mitochondria in a renal or cardiac cell (e.g., myocardialmuscle cell). In another variation, the disease or condition is onewhich would benefit from cellular (e.g., renal or cardiac) nutrientinflux and/or oxygenation.

Thus, individuals who have a disease or condition that is associatedwith, or believed to be associated with, mitochondrial dysfunction maybenefit from the compounds detailed herein, or pharmaceuticallyacceptable salts thereof. An individual who has a disease or conditionthat is associated with mitochondrial dysfunction should experience oneor more beneficial or desirable results upon administration of aneffective amount of a compound provided herein, or pharmaceuticallyacceptable salt thereof. In one aspect, the beneficial or desirableresult is an increase in nutrient influx and/or oxygenation of a cell.In another aspect, the beneficial or desirable result is a reduction inthe number and/or severity of symptoms associated with a disease orcondition that is associated with mitochondrial dysfunction.

In one variation, a method of treating a renal or cardiac condition isprovided, comprising administering to an individual in need thereof acompound as detailed herein. Such conditions include, but are notlimited to, renal failure, such as acute renal failure and chronic renalfailure, coronary (e.g., myocardial) ischemia, heart failure, such asacute and chronic congestive heart failure (including the muscle fatigueassociated with these conditions), and coronary artery disease. Methodsof treating other diseases and conditions are also described, such asmethods of treating sleep apnea, acute respiratory distress syndrome(adult and infant) and peripheral vascular disease. The compounds asprovided herein may also be used in a method of delaying the onsetand/or development of a disease or condition associated withmitochondrial dysfunction, comprising administering a compound asprovided herein, or a pharmaceutical salt thereof, to an individual whois at risk of developing a disease or condition associated withmitochondrial dysfunction.

Compounds that do not bind appreciably to neurotransmitter receptors butnevertheless enhance mitochondrial function, e.g., when administered tocells in the setting of mitochondrial stress (e.g., excess intracellularcalcium), may be used in the methods herein to promote cell survival. Inone aspect, the compounds exhibit the ability to enhance mitochondrialfunction by protecting against cell death mediated by mitochondrialdysfunction in an assay detailed herein. Thus, it is understood andclearly conveyed that enhancing mitochondrial function includesprotecting a cell against cell death mediated by mitochondrialdysfunction. The compounds may also be assessed in assays known in theart.

It is understood and clearly conveyed that the binding and activityprofiles detailed herein (e.g., in the disclosure above) in onevariation apply to the formulae provided herein (e.g., the formulae foruse in the methods). In one aspect, selective adrenergic receptor α_(2B)antagonists are of the formula (I), (A-I), (A-IIA), (A-IIB), (A-IIC),(A-IID), (A-IIA-1), (A-IIB-1), (A-IIC-1), (A-IID-1), (A-III), (A-IIIA),(A-IIIB), (A-IIIC), (A-IIID), (A-IIIE), (A-IIIE-1), (A-IIIE-2),(A-IIIE-3), (A-IIIE-4), (A-IIIE-5), (A-IIIE-6), (A-IIIE-7), (A-IIIE-8),(A-IIIF), (A-IIIF-1), (A-IIIF-2), (A-IIIF-3), (A-IIIF-4), (A-IIIG-1),(A-IIIG-2), (A-IIIG-3), (A-IIIH), (A-IIIH-1), (A-IIIH-2), (A-IIIH-3),(A-IIIH-4), (A-IIIA′), (A-IV), (A-V), (A-VI), (A-VIIA), (A-VIIB),(A-VIIC), (A-VIID), (A-VIIE), (A-VIIF), (A-VIIIA-1), (A-VIIIA-2),(A-VIIIA-3), (A-VIIIA-4), (A-VIIIA-5), (A-VIIIA-6), (A-VIIIA-7),(A-IXA), (A-IXB), (A-IXC), (A-IXD), (B-I), (B-IA), (B-IB), (B-IC),(B-ID), (C-I), (C-IA), (C-IB), (C-IA-1), (C-IA-2), (C-IA-3), (C-IA-4),(C-IA-5), (C-IA-6), (C-IA-7), (C-IB), (C-IB-1), (C-IB-2), (C-IB-3),(C-IC-1), (C-II), (C-IIA), (C-IIB), (C-IIIA), (C-IIIB), (C-IIIC),(C-IIID), (CIII-E), (C-IIIF), (C-IVA), (C-IVB), (C-IVC), (C-IVD),(C-IVE), (C-IVF), (C-IVG), (C-VA), (C-VB), (D-I), (D-IIA), (D-IIB),(D-IIA-1), (D-IIA-2), (D-IIIA), (D-IIIB), (E-I), (E-IIA), (E-IIB),(F-I), (F-IIA), (F-IIB), (F-IIA-1), (F-IIA-2), (G-I), (G-IIA), (G-IIB),(G-IIA-1), (G-IIA-2), (H-IA), (H-IB), (H-IC), (H-ID), (H-IA-1),(H-IB-1), (H-IC-1), (H-ID-1), (H-IE-1), (H-IF-1), (J), (J-IA), (J-IB),(J-IC), (J-ID), (J-IA-1), (J-IB-1), (J-IC-1), (J-ID-1), (K-IA), (K-IB),(K-IC), (K-ID), (K-IE) or (K-IF), or any variations detailed herein.

Compounds of the Invention

Compounds according to the invention are detailed herein, including inthe Brief Summary of the Invention and elsewhere. The invention includesthe use of all of the compounds described herein, including any and allstereoisomers, including geometric isomers (cis/trans or E/Z isomers),tautomers, salts, N-oxides, and solvates of the compounds describedherein, as well as methods of making such compounds.

In one aspect, provided is a compound of formula (I):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H; C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, hydroxyl,carboxyl, SO₃H, SR^(1a), S(O)R^(1a), SO₂R^(1a) and perhaloalkyl; C₃-C₈cycloalkyl optionally substituted with 1 to 3 substituents independentlyselected from the group consisting of halo, hydroxyl, carboxyl andperhaloalkyl; C₂-C₅ alkenyl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,hydroxyl, carboxyl and perhaloalkyl; or —C(O)O—C₁-C₅ alkyl; or is takentogether with R^(2a) or R^(3a) to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(4a)or R^(5a), where present, to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety;

R^(1a) is H or optionally substituted C₁-C₅ alkyl;

R^(2a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR¹ or R^(5a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety ora butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(3a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;or is taken together with R^(4a), where present, to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(3a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR¹ or R^(4a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety ora butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(2a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;or is taken together with R^(5a), where present, to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(4a), where present, is H; halo; hydroxyl; cyano; carboxyl;—OC(O)N(R^(14a))R^(15a); —C(O)N(R^(14a))R^(15a); optionally substitutedC₁-C₅ alkyl; optionally substituted C₂-C₅ alkenyl; or optionallysubstituted aryl; or is taken together with R^(3a) to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; or is takentogether with R¹ to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety; or is taken together with R^(2a) to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety; or is takentogether with R^(5a), where present, to form a methylene (—CH₂—) moiety;

R^(5a), where present, is H; halo; hydroxyl; cyano; carboxyl;—OC(O)N(R^(14a))R^(15a); —C(O)N(R^(14a))R^(15a); optionally substitutedC₁-C₅ alkyl; optionally substituted C₂-C₅ alkenyl; or optionallysubstituted aryl; or is taken together with R^(2a) to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; or is takentogether with R¹ to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety; or is taken together with R^(3a) to form amethylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety; or is takentogether with R^(4a), where present, to form a methylene (—CH₂—) moiety;

each R^(2b) and R^(3b) is independently H, optionally substituted C₁-C₅alkyl, optionally substituted C₂-C₅ alkenyl, or optionally substitutedaryl;

each R^(4b) and R^(5b), where present, is independently H, halo,optionally substituted C₁-C₅ alkyl, optionally substituted C₂-C₅alkenyl, or optionally substituted aryl;

each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0;

each X¹, X², X and U is independently N or CR⁶;

each R⁶ is independently H; hydroxyl; halo; C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxyl, carboxyl and perhaloalkyl; C₂-C₅alkenyl; optionally substituted C₁-C₅ alkoxy; or optionally substituted—C(O)C₁-C₅ alkyl;

R⁷ is H; halo; optionally substituted C₁-C₅ alkyl; or optionallysubstituted aryl; or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;or is taken together with R⁹ to form a C₃-C₅ alkylene when R⁸ and R¹⁰are taken together to form a bond;

R⁸ is H; halo; hydroxyl; azido; aminoacyl, carboxyl; carbonylalkoxy;N(R¹¹)R¹²; SR¹³S(O)R¹³; SO₂R¹³; —OC(O)N(R¹⁴)R¹⁵; —C(O)N(R¹⁴)R¹⁵;optionally substituted —OC(O)-aryl; optionally substituted—OC(O)-heteroaryl; —OC(O)C₁-C₆ alkyl optionally substituted with aminoor carboxyl; or —OC₁-C₅ alkyl optionally substituted with carboxyl; oris taken together with R⁷ and the carbon atom to which they are attachedto form a dioxolane ring or a carbonyl moiety; or is taken together withR¹⁰ to form a bond;

R⁹ is H or optionally substituted C₁-C₅ alkyl, or is taken together withR⁷ to form a C₃-C₅ alkylene when R⁸ and R¹⁰ are taken together to form abond;

R¹⁰ is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R⁸ to form a bond;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene;

each R^(14a), and R^(15a) is independently H or optionally substitutedC₁-C₅ alkyl; and

Q is optionally substituted cycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl.

It should be understood that when two substituents are taken together toform a bond, an additional bond is formed. For example, as shown below,when R^(y) and R^(w) are taken together to form a bond, an additionalbond is formed such that Rx and R^(z) is a double bond.

In some variations, one of X¹, X², X and U is N, and the other three ofX¹, X², X and U are independently CR⁶. In other variations, two of X¹,X², X and U is N, and the other two of X¹, X², X and U are independentlyCR⁶. In yet other variations, each X¹, X², X and U is independently CR⁶.

In some variations, R¹ is H, optionally substituted C₁-C₅ alkyl, oroptionally substituted C₃-C₈ cycloalkyl, wherein the C₁-C₅ alkyl or theC₃-C₈ cycloalkyl is independently unsubstituted or substituted withhydroxyl. In some variations, R¹ is unsubstituted C₂-C₅ alkenyl. Inother variations, the C₁-C₅ alkyl is substituted with SO₃H. In somevariations, R¹ is methyl, ethyl, n-propyl, or i-propyl. In somevariations, R¹ is CF₃, or CH₂CF₃. In some variations R¹ is H. In somevariations, R¹ is hydroxyethyl, hydroxypropyl, or hydroxybutyl. In somevariations, R¹ is cyclobutyl, or cyclopropyl. In some variations, R¹ isCH₂CH₂—SO₃H. In some variations, R¹ is CH₂CH═CH₂.

In some variations, R^(4a) is halo; hydroxyl; cyano; carboxyl;—OC(O)N(R^(14a))R^(15a)); —C(O)N(R^(14a))R^(15a); optionally substitutedC₁-C₅ alkyl. In some embodiments, R^(4a) is optionally substituted C₁-C₅alkyl. In other embodiments, R^(4a) is monohaloalkyl, dihaloalkyl, orperhaloalkyl. In one embodiment, R^(4a) is CF₃, CHF₂, or CH₂F. Inanother embodiment, R^(4a) is CCl₃, CHCl₂, or CH₂Cl. In some variations,R^(4a) is halo. In some variations, R^(4a) and R^(4b) are each halo. Incertain variations, each R^(4a) and R^(4b) is fluoro or chloro. In onevariation, each R^(4a) and R^(4b) is fluoro. In one variation, eachR^(4a) and R^(4b) is chloro.

In some variations, R^(5a) is halo; hydroxyl; cyano; carboxyl;—OC(O)N(R^(14a))R^(15a); —C(O)N(R^(14a))R^(15a); optionally substitutedC₁-C₅ alkyl. In some embodiments, R^(5a) is optionally substituted C₁-C₅alkyl. In other embodiments, R^(5a) is monohaloalkyl, dihaloalkyl, orperhaloalkyl. In one embodiment, R^(5a) is CF₃, CHF₂, or CH₂F. Inanother embodiment, R^(5a) is CCl₃, CHCl₂, or CH₂Cl. In some variations,R^(5a) is halo. In some variations, R^(5a) and R^(5b) are each halo. Incertain variations, each R^(5a) and R^(5b) is fluoro or chloro. In onevariation, each R^(5a) and R^(5b) is fluoro. In one variation, eachR^(5a) and R^(5b) is chloro.

In some variations, R⁷ is a C₁-C₅ alkyl optionally substituted with 1 to3 substituents independently selected from the group consisting of halo,hydroxyl, —N(R^(7a))(R^(7b)), —C(O)N(R^(7a))(R^(7b)), —C(O)OR^(7a), and—C(O)R^(7a). In other variations, R⁷ is an optionally substituted C₃-C₈cycloalkyl. In some variations, R⁸ is hydroxyl or NH₂. In somevariations, R⁸ is —OC(O)C₁-C₅ alkyl optionally substituted with amino orcarboxyl. In some variations, R⁸ is taken together with R¹⁰ to form abond. In some variations, R⁹ is H or CH₃. In some variations, in R¹⁰ isH or CH₃. In some variations, each R⁹ and R¹⁰ is H. In some variations,R¹⁰ is an optionally substituted C₃-C₈ cycloalkyl. In other variations,R¹¹ or R¹² is an optionally substituted C₃-C₈ cycloalkyl.

In some variations, Q is unsubstituted aryl; unsubstituted heteroaryl;aryl substituted with 1 to 3 substituents independently selected fromthe group consisting of halo, hydroxyl, C₁-C₅ alkyl, C₃-C₈ cycloalkyl,halo-substituted C₁-C₅ alkyl, halo-substituted C₃-C₈ cycloalkyl, C₁-C₅alkoxy, C₃-C₈ cycloalkoxy, cyano, carboxyl, aminoacyl, N(R¹⁶)(R¹⁷),—C(O)OR¹⁸, SR¹⁸, S(O)R¹⁸ and SO₂R¹⁸; or heteroaryl substituted with 1 to3 substituents independently selected from the group consisting of halo,hydroxyl, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl, N(R¹⁶)(R¹⁷), —C(O)OR¹⁸, SR¹⁸, S(O)R¹⁸ andSO₂R¹⁸, wherein each R¹⁶ and R¹⁷ is independently H or optionallysubstituted C₁-C₅ alkyl, or R¹⁶ and R¹⁷ are taken together to form C₃-C₅alkylene, and wherein R¹⁸ is an optionally substituted C₁-C₅ alkyl.

In one embodiment of the compound of formula (I):

R¹ is H; C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl;C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl;C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl;or —C(O)O—C₁-C₅ alkyl, or is taken together with R^(2a) or R^(3a) toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(4a) is selected from the group consisting of halo, hydroxyl, cyano,carboxyl, —OC(O)N(R^(14a))R^(15a), —C(O)N(R^(14a))R^(15a), andoptionally substituted C₁-C₅ alkyl;

each R^(2b) and R^(3b) is independently H;

R^(4b) is H, halo, optionally substituted C₁-C₅ alkyl;

n is 0 and m is 1;

each X¹, X², and U is CH;

X is independently N or CR^(6a);

each R⁶ and R^(6a) is independently H; hydroxyl; halo; C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl;C₂-C₅ alkenyl; optionally substituted C₁-C₅ alkoxy; or optionallysubstituted —C(O)C₁-C₅ alkyl;

R⁷ is H; halo; optionally substituted C₁-C₅ alkyl; or optionallysubstituted aryl; or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;or is taken together with R⁹ to form a C₃-C₅ alkylene when R⁸ and R¹⁰are taken together to form a bond;

R⁸ is H; halo; hydroxyl; azido; aminoacyl, carboxyl; carbonylalkoxy;N(R¹¹)R¹²; SR¹³S(O)R¹³; SO₂R¹³; —OC(O)N(R¹⁴)R¹⁵; —C(O)N(R¹⁴)R¹⁵;optionally substituted —OC(O)-aryl; optionally substituted—OC(O)-heteroaryl; —OC(O)C₁-C₆ alkyl optionally substituted with aminoor carboxyl; or —OC₁-C₅ alkyl optionally substituted with carboxyl; oris taken together with R⁷ and the carbon atom to which they are attachedto form a dioxolane ring or a carbonyl moiety; or is taken together withR¹⁰ to form a bond;

R⁹ is H or optionally substituted C₁-C₅ alkyl, or is taken together withR⁷ to form a C₃-C₅ alkylene when R⁸ and R¹⁰ are taken together to form abond;

R¹⁰ is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R⁸ to form a bond;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

Q is cycloalkyl, aryl or heteroaryl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, C₃-C₅ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In some embodiments, R^(4a) is an optionally substituted C₁-C₅ alkyl. Incertain embodiments, R^(4a) is a monohaloalkyl, a dihaloalkyl, orperhaloalkyl. In some variations, R^(4a) is halo, hydroxyl, and cyano.In some variations, R^(4a) is halo. In some variations, R^(4a) andR^(4b) are each halo. In certain variations, each R^(4a) and R^(4b) isfluoro or chloro. In one variation, each R^(4a) and R^(4b) is fluoro.

In certain embodiments, with respect to the compounds of formula (I), Xis CR⁶, R⁸ is —OC(O)C₁-C₅ alkyl substituted with carboxyl, and thecompound is Compound No. 25, 54, 130, 146, 147, 338, II-15, II-16, orII-19.

In certain embodiments, with respect to the compounds of formula (I), R⁸is azido, and the compound is Compound No. II-261, II-266, II-276,II-298, V-1, V-2, V-3, V-21, V-22, or V-23.

In one embodiment, the compound is of formula (A-I):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl or cycloalkyl optionally substituted with 1 to 3halogen atoms or hydroxyl, C₂-C₅ alkenyl, or —C(O)OR¹¹;

each R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a) and R^(5b)is independently H or optionally substituted C₁-C₅ alkyl;

each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0;

or R¹ and R^(2a), or R¹ and R^(3a), or R^(2a) and R^(5a), or R^(3a) andR^(4a), where present, are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety,

or R¹ and R^(4a), or R¹ and R^(5a), or R^(2a) and R^(3a), where present,are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety,

or R^(2a) and R^(4a), or R^(3a) and R^(5a), where present, are takentogether to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety,

or R^(4a) and R^(5a), where present, are taken together to form amethylene (—CH₂—) moiety;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, halogen, C₁-C₅ alkyl optionallysubstituted with 1 to 3 halogen atoms, hydroxyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

each R⁷, R⁹ and R¹⁰ is independently H or optionally substituted C₁-C₅alkyl;

R⁸ is H, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³, or —OC(O)C₁-C₅alkyl optionally substituted with amino;

or R⁷ and R⁸ are taken together with the carbon atom to which they areattached to form a dioxolane ring or a carbonyl moiety;

or R¹⁰ and R⁸ are taken together to form a bond;

or R⁹ and R⁷ are taken together to form an alkylene bridge of 3-5 carbonatoms when R¹⁰ and R⁸ are taken together to form a bond;

each R¹¹, R¹² and R¹³ is independently H or optionally substituted C₁-C₅alkyl; and

Q is aryl or heteroaryl optionally substituted with 1 to 3 substituentsincluding halogen, C₁-C₅ alkyl or cycloalkyl, halo-substituted C₁-C₅alkyl or cycloalkyl, C₁-C₅ alkoxy or cycloalkoxy, —CN or—C(O)N(R^(a))R^(b) where each R^(a) and R^(b) is independently H orC₁-C₅ alkyl.

In another embodiment, the compound is of the formula (A-IIA), (A-IIB),(A-IIC) or (A-IID):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl or cycloalkyl optionally substituted with 1 to 3halogen atoms or hydroxyl, C₂-C₅ alkenyl, or —C(O)OR¹¹;

each R^(2a), R^(3a) or R^(5a) is independently H or optionallysubstituted C₁-C₅ alkyl;

or R¹ and R^(2a), or R¹ and R^(3a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, halogen, C₁-C₅ alkyl optionallysubstituted with 1 to 3 halogen atoms, hydroxyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

each R⁷, R⁹ and R¹⁰ is independently H or optionally substituted C₁-C₅alkyl;

R⁸ is H, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³, or —OC(O)C₁-C₅alkyl optionally substituted with amino;

or R⁷ and R⁸ are taken together with the carbon atom to which they areattached to form a dioxolane ring or a carbonyl moiety;

or R¹⁰ and R⁸ are taken together to form a bond;

or R⁹ and R⁷ are taken together to form an alkylene bridge of 3 to 5carbon atoms when R¹⁰ and R⁸ are taken together to form a bond;

each R¹¹, R¹² and R¹³ is independently H or optionally substituted C₁-C₅alkyl; and

Q is aryl or heteroaryl optionally substituted with 1 to 3 substituentsincluding halogen, C₁-C₅ alkyl or cycloalkyl, halo-substituted C₁-C₅alkyl or cycloalkyl, C₁-C₅ alkoxy or cycloalkoxy, —CN, —CO₂H or—C(O)N(R^(a))R^(b), wherein each R^(a) and R^(b) is independently H orC₁-C₅ alkyl.

In some embodiments, the compound is of formula (A-IIA). In somevariations, X is CR^(6a), wherein R^(6a) is H. In some variations, R⁶ isH. In other variations, R¹ is H or CH₃. In yet other variations, R⁷ is Hor CH₃. In yet other variations, R⁸ is hydroxyl. In yet othervariations, Q is optionally substituted pyridyl, optionally substitutedpyrimidyl, optionally substituted pyrazinyl, or optionally substitutedphenyl.

In some embodiments, the compound is of formula (A-IIB). In somevariations, X is CR^(6a), wherein R^(6a) is H. In some variations, R⁶ isH. In other variations, R¹ is H or CH₃. In yet other variations, R⁷ is Hor CH₃. In yet other variations, R⁸ is hydroxyl. In yet othervariations, Q is optionally substituted pyridyl, optionally substitutedpyrimidyl, optionally substituted pyrazinyl, or optionally substitutedphenyl.

In one embodiment, the compound is of formula (A-IA):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl or cycloalkyl optionally substituted with 1 to 3halogen atoms or hydroxyl, C₂-C₅ alkenyl, or —C(O)OR¹¹;

each R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a) and R^(5b)is independently H or optionally substituted C₁-C₅ alkyl;

each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0;

or R¹ and R^(2a), or R¹ and R^(3a), or R^(2a) and R^(5a), or R^(3a) andR^(4a), where present, are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety,

or R¹ and R^(4a), or R¹ and R^(5a), or R^(2a) and R^(3a), where present,are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety,

or R^(2a) and R^(4a), or R^(3a) and R^(5a), where present, are takentogether to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety,

or R^(4a) and R^(5a), where present, are taken together to form amethylene (—CH₂—) moiety;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, halogen, C₁-C₅ alkyl optionallysubstituted with 1 to 3 halogen atoms, hydroxyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

each R⁷, R⁹ and R¹⁰ is independently H or optionally substituted C₁-C₅alkyl;

R⁸ is N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³, or —OC(O)C₁-C₅ alkyl optionallysubstituted with amino;

each R¹¹, R¹² and R¹³ is independently H or optionally substituted C₁-C₅alkyl; and

Q is aryl or heteroaryl optionally substituted with 1 to 3 substituentsincluding halogen, C₁-C₅ alkyl or cycloalkyl, halo-substituted C₁-C₅alkyl or cycloalkyl, C₁-C₅ alkoxy or cycloalkoxy, —CN, —CO₂H or—C(O)N(R^(a))R^(b), wherein each R^(a) and R^(b) is independently H orC₁-C₅ alkyl.

In one aspect, the present invention provides compounds according toformula (A-IB), (A-IC) or (A-ID):

wherein Q, R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a),R^(5b), R⁶, R⁷, R⁸, m, and n are as described for formula (A-I), above;and each X¹, U, X² and X is independently CR⁶.

In certain embodiments, with respect to the compounds of formula (A-IB),R⁷ is optionally substituted cycloalkyl; R⁸ is OH; R¹ is methyl; n is 0;each of R^(2b), R^(3a), R^(3b), R^(4b), R⁹, and R¹⁰ is H; each R^(2a)and R^(4a) is H; or R^(2a) taken together with R^(4a), when present, toform an ethylene (—CH₂CH₂—) moiety; each X¹, X² and X is CH, U is CR⁶,and R⁶ is methyl or chloro; and Q is other than unsubstituted phenyl,phenyl substituted with F, or unsubstituted pyridyl.

In certain embodiments, with respect to the compounds of formula (A-IB),R⁷ is C₁-C₅ alkyl substituted with acylamino. In one embodiment, R⁷ isCH₂—CON(H)CH₃; R¹ is methyl or ethyl; n is 0; each of R^(2b), R^(3a),R^(3b), R^(4b), R⁹ and R¹⁰ is H; each R^(2a) and R^(4a) is H; or R^(2a)taken together with R^(4a), when present, to form an ethylene (—CH₂CH₂—)moiety; each X¹, X² and X is CH, U is CR⁶, and R⁶ is methyl or chloro;and Q is other than phenyl substituted with fluoro, chloro, methoxy, ordifluoro, unsubstituted pyridyl, pyridyl substituted with methyl, orunsubstituted pyrimidinyl

In certain embodiments, with respect to the compounds of formula (A-IB),R⁷ is C₁-C₅ alkyl substituted with —C(O)OR^(7a), wherein R^(7a) is H oroptionally substituted C₁-C₅ alkyl; R¹ is methyl or ethyl; n is 0; eachof R^(2b), R^(3a), R^(3b) and R^(4b) is H; each R^(2a) and R^(4a) is H;or R^(2a) taken together with R^(4a), when present, to form an ethylene(—CH₂CH₂—) moiety; each X¹, X² and X is CH, U is CR⁶, and R⁶ is methylor chloro; and Q is other than phenyl substituted with fluoro, chloro,methoxy, or difluoro, unsubstituted pyridyl, pyridyl substituted withmethyl, or unsubstituted pyrimidinyl.

In certain embodiments, with respect to the compounds of formula (A-IB),R⁷ is C₁-C₅ alkyl substituted with 1 to 3 halo; R⁷ is CF₃′ R⁸ is OH; R¹is methyl; n is 0; each of R^(2b), R^(3a), R^(3b) and R^(4b) is H; eachR^(2a) and R^(4a) is H; or R^(2a) taken together with R^(4a), whenpresent, to form an ethylene (—CH₂CH₂—) moiety; each X¹, X² and X is CH,U is CR⁶, and R⁶ is methyl; and Q is other than phenyl substituted withfluoro.

In certain embodiments, with respect to the compounds of formula (A-IB),R⁷ is optionally substituted phenyl; R⁸ is OH; R¹ is methyl or ethyl; nis 0; each of R^(2b), R^(3a), R^(3b) and R^(4b) is H; each R^(2a) andR^(4a) is H; or R^(2a) taken together with R^(4a), when present, to forman ethylene (—CH₂CH₂—) moiety; each X¹, X² and X is CH, U is CR⁶, and R⁶is methyl or chloro; and Q is other than unsubstituted phenyl, phenylsubstituted with fluoro or unsubstituted pyridyl.

In certain embodiments, with respect to the compounds of formula (A-IB),R⁸ is halo. In one embodiment, R⁸ is fluoro or chloro; R¹ is methyl,ethyl, isopropyl, or cyclopropyl; n is 0; each of R^(2b), R^(3a), R^(3b)and R^(4b) is H; each R^(2a) and R^(4a) is H; or R^(2a) taken togetherwith R^(4a), when present, to form an ethylene (—CH₂CH₂—) moiety; R⁷ isH or methyl; each X¹, X² and X is CH, U is CR⁶, and R⁶ is methyl orchloro; and Q is other than unsubstituted phenyl, phenyl substitutedwith methoxy, chloro, fluoro, difluoro, unsubstituted pyridyl, pyridylsubstituted with methyl, or unsubstituted pyrimidinyl.

In certain embodiments, with respect to the compounds of formula (A-IB),R⁸ is —C(O)N(R¹⁴)R¹⁵; and each R¹⁴ and R¹⁵ is independently H oroptionally substituted C₁-C₅ alkyl; or R¹⁴ and R¹⁵ are taken together toform a C₃-C₅ alkylene; R¹ is methyl; n is 0; each of R^(2b), R^(3a),R^(3b) and R^(4b) is H; each R^(2a) and R^(4a) is H; or R^(2a) takentogether with R^(4a), when present, to form an ethylene (—CH₂CH₂—)moiety; each X¹, X² and X is CH, U is CR⁶, and R⁶ is methyl; and Q isother than cyclobutyl.

In certain embodiments, with respect to the compounds of formula (A-IB),R⁸ is —OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, —OC(O)C₁-C₅ alkyloptionally substituted with amino, —OC(O)C₁-C₅ alkyl substituted withcarboxyl, or —OC₁-C₅ alkyl optionally substituted with carboxyl; andeach R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl, or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene.

In certain embodiments, with respect to the compounds of formula (A-IC),Q is optionally substituted 5-membered heteroaryl; n is 0; R⁷ is fluoroor methyl; R¹ is methyl; each of R^(2a), R^(2b), R^(3a), R^(3b), R^(4a)and R^(4b) is H; each X¹, X² and X is CH, U is CR⁶, and R⁶ is methyl orchloro; and Q is other than unsubstituted thienyl or unsubstitutedthiazolyl.

In certain embodiments, with respect to the compounds of formula (A-IC),Q is optionally substituted pyridyl, each of R^(2a), R^(2b), R^(3a),R^(3b), R^(4a) and R^(4b) is H; each X¹, X² and X is CH, U is CR⁶, andR⁶ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted C₁-C₅ alkoxy; and Q is other than unsubstituted pyridyl, orpyridyl substituted with methyl, chloro, bromo, methoxy, or dimethyl.

In certain embodiments, with respect to the compounds of formula (A-IC),Q is optionally substituted pyrimidinyl; R¹ is methyl; each of R^(2a),R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) is H; each X¹, X² and X is CH,U is CR⁶, and R⁶ is methyl or chloro; and Q is other than unsubstitutedpyrimidin-4-yl, pyrimidin-4-yl substituted with methyl, unsubstitutedpyrimidin-5-yl, or pyrimidin-5-yl substituted with methyl.

In certain embodiments, with respect to the compounds of formula (A-ID),each of R^(2b), R^(3a), R^(3b), R^(4b), R^(5a) and R^(5b) is H; eachR^(2a) and R^(4a) is H; or R^(2a) taken together with R^(4a), wherepresent, an ethylene (—CH₂CH₂—) moiety; U is CR⁶, and R⁶ is selectedfrom the group consisting of CF₃, methyl, Cl, CONHCH₃, COOH, COOCH₃, Hand F; then R¹ is other than methyl.

In certain embodiments, with respect to the compounds of formula (A-ID),each of R^(2b), R^(3a), R^(3b), R^(4b), R^(5a) and R^(5b) is H; eachR^(2a) and R^(4a) is H; or R^(2a) taken together with R^(4a), wherepresent, an ethylene (—CH₂CH₂—) moiety; X is CR⁶, and R⁶ is F; then R¹is other than methyl.

In certain embodiments, with respect to the compounds of formula (A-IB),(A-IC), or (A-ID), n is 0. In certain embodiments, with respect to thecompounds of formula (A-IB), (A-IC), or (A-ID), n is 1. In certainembodiments, with respect to the compounds of formula (A-IB), (A-IC), or(A-ID), m is 0. In certain embodiments, with respect to the compounds offormula (A-IB), (A-IC), or (A-ID), m is 1.

In certain embodiments, with respect to the compounds of formula (A-IB),(A-IC), or (A-ID), each R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b),R^(5a), and R^(5b) is H.

In certain embodiments, with respect to the compounds of formula (A-IB),(A-IC), or (A-ID), R^(2a) together with R¹ form a butylene or propylenemoiety.

In certain embodiments, with respect to the compounds of formula (A-IB),(A-IC), or (A-ID), R^(2a) together with R^(3a) form a propylene orethylene moiety.

In certain embodiments, with respect to the compounds of formula (A-IB),(A-IC), or (A-ID), R^(2a) together with R^(4a) form a propylene orethylene moiety.

In certain embodiments, with respect to the compounds of formula (A-IB),(A-IC), or (A-ID), R^(5a) together with R^(3a) form a methylene orethylene moiety.

In certain embodiments, with respect to the compounds of formula (A-IB),(A-IC), or (A-ID), R^(2a) together with R^(4a) form a methylene orethylene moiety.

In certain embodiments, with respect to the compounds of formula (A-IB),(A-IC), or (A-ID), R^(3a) together with R¹ form a butylene or propylenemoiety.

In one embodiment, the present invention provides compounds according toformula (A-IE):

wherein X¹, U, X², X, Q, R¹, R⁶, R⁷ and R⁸ are as described for formula(A-IB).

In another embodiment, the compound is of the formula (A-IIA-1),(A-IIB-1), (A-IIC-1) or (A-IID-1):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl or cycloalkyl optionally substituted with 1 to 3halogen atoms or hydroxyl, C₂-C₅ alkenyl, or —C(O)OR¹¹;

each R^(2a), R^(3a) or R^(5a) is independently H or optionallysubstituted C₁-C₅ alkyl;

or R¹ and R^(2a), or R¹ and R^(3a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, halogen, C₁-C₅ alkyl optionallysubstituted with 1 to 3 halogen atoms, hydroxyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

each R⁷, R⁹ and R¹⁰ is independently H or optionally substituted C₁-C₅alkyl;

R⁸ is H, azido, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³, or—OC(O)C₁-C₅ alkyl optionally substituted with amino;

each R¹¹, R¹² and R¹³ is independently H or optionally substituted C₁-C₅alkyl; and

Q is aryl or heteroaryl optionally substituted with 1 to 3 substituentsincluding halogen, C₁-C₅ alkyl or cycloalkyl, halo-substituted C₁-C₅alkyl or cycloalkyl, C₁-C₅ alkoxy or cycloalkoxy, —CN or—C(O)N(R^(a))R^(b) where each R^(a) and R^(b) is independently H orC₁-C₅ alkyl.

In one variation, each R⁶ and R^(6a) is independently H, CH₃ or Cl.

In one variation, R⁸ is H, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,or —OC(O)C₁-C₅ alkyl optionally substituted with amino, where R¹¹, R¹²and R¹³ are each independently H or optionally substituted C₁-C₅ alkyl.In a particular variation, R⁸ is H, OH, NH₂, —OC(O)CH(NH₂)—CH₃,—OC(O)CH(NH₂)—CH(CH₃)₂, and —OC(O)CH(NH₂)—CH₃—CH(CH₃)₂.

In one variation, R¹⁰ and R⁸ are taken together to form a bond.

In one variation, R¹⁰ and R⁸ are taken together to form a bond, and R⁷and R⁹ are taken together to form an alkylene bridge of 3 to 5 carbonatoms.

In one embodiment, the compound is of formula (A-IIA-1). In somevariations, X is CR^(6a) wherein R^(6a) is H. In other variations, R⁶ isH. In other variations, R¹ is H or CH₃. In yet other variations, R⁷ is Hor CH₃. In yet other variations, R⁸ is hydroxyl or NH₂. In yet othervariations, Q is optionally substituted pyridyl, optionally substitutedpyrimidyl, optionally substituted pyrazinyl, or optionally substitutedphenyl.

In another embodiment, the compound is of formula (A-IID-1). In somevariations, X is CR⁶, wherein R⁶ is H. In other variations, R¹ is H orCH₃. In yet other variations, R⁷ is H or CH₃. In yet other variations,R⁸ is hydroxyl or NH₂. In yet other variations, Q is optionallysubstituted pyridyl, optionally substituted pyrimidyl, optionallysubstituted pyrazinyl, or optionally substituted phenyl.

In another embodiment, the compound is of formula (A-III):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H; C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, hydroxyl,carboxyl and perhaloalkyl; C₃-C₈ cycloalkyl optionally substituted with1 to 3 substituents independently selected from the group consisting ofhalo, hydroxyl, carboxyl and perhaloalkyl; C₂-C₅ alkenyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxyl, carboxyl and perhaloalkyl; or—C(O)O—C₁-C₅ alkyl; or is taken together with R^(2a) or R^(3a) to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; oris taken together with R^(4a) or R^(5a), where present, to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;

each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0;

R^(2a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR¹ or R^(5a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety ora butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(3a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;or is taken together with R^(4a), where present, to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(3a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR¹ or R^(4a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety ora butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(2a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;or is taken together with R^(5a), where present, to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(4a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR^(3a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R¹ to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety; or istaken together with R^(2a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety; or is taken together with R^(5a), wherepresent, to form a methylene (—CH₂—) moiety;

R^(5a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR^(2a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R¹ to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety; or istaken together with R^(3a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety; or is taken together with R^(4a), wherepresent, to form a methylene (—CH₂—) moiety;

each R^(2b), R^(3b), R^(4b) and R^(5b) is independently H, optionallysubstituted C₁-C₅ alkyl, optionally substituted C₂-C₅ alkenyl, oroptionally substituted aryl;

X is N or CR^(6a);

t is 1, 2 or 3;

each R⁶ and R^(6a) is independently H; hydroxyl; halo; C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl;C₂-C₅ alkenyl; optionally substituted C₁-C₅ alkoxy; or optionallysubstituted —C(O)C₁-C₅ alkyl;

R⁷ is H; halo; optionally substituted C₁-C₅ alkyl; or optionallysubstituted aryl; or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;or is taken together with R⁹ to form a C₃-C₅ alkylene when R⁸ and R¹⁰are taken together to form a bond;

R⁸ is H; halo; hydroxyl; N(R¹¹)R¹²; SR¹³, S(O)R¹³; SO₂R¹³;—OC(O)N(R¹⁴)R¹⁵; —OC(O)-aryl; —OC(O)-heteroaryl; or —OC(O)C₁-C₅ alkyloptionally substituted with amino; or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety; or is taken together with R¹⁰ to form a bond;

R⁹ is H or optionally substituted C₁-C₅ alkyl; or is taken together withR⁷ to form a C₃-C₅ alkylene when R⁸ and R¹⁰ are taken together to form abond;

R¹⁰ is H or optionally substituted C₁-C₅ alkyl; or is taken togetherwith R⁸ to form a bond;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl; or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

Q is unsubstituted aryl; unsubstituted heteroaryl; aryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino; or heteroaryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In some variations, Q is unsubstituted aryl; unsubstituted heteroaryl;aryl substituted with halo, CH₃, CF₃, or OCH₃; or heteroaryl substitutedwith halo, CH₃, CF₃, or OCH₃. In other variations, Q is unsubstitutedpyridyl; unsubstituted pyrimidyl; unsubstituted pyrazinyl; unsubstitutedphenyl; pyridyl substituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃;pyrimidyl substituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃; pyrazinylsubstituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃; or phenylsubstituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃.

In one variation, the compound is of the formula (A-III), wherein Q, X,m, n, t, R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a),R^(5b), R⁶, R^(6a), R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are as defined for theformula (A-III), R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, R⁸is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³, —OC(O)N(R¹⁴)R⁵,or —OC(O)C₁-C₅ alkyl optionally substituted with amino, and each R⁹ andR¹⁰ is independently H or optionally substituted C₁-C₅ alkyl; or a salt,solvate or N-oxide thereof.

In some variations of the compound of the formula (A-III), R¹ is C₁-C₅alkyl (e.g., methyl), each R^(2a) and R^(3a) is H, R⁶ is methyl orchloro, and X is CR^(6a) where R^(6a) is methyl or chloro. In some ofthese variations, t is 1, 2 or 3. In some of these variations, R⁷ is Hor C₁-C₅ alkyl (e.g., methyl) and R⁸ is H or hydroxyl. In some of thesevariations, each R⁷ and R⁸ is H. In some of these variations, R⁹ is H orC₁-C₅ alkyl (e.g., methyl) and R¹⁰ is H. In some of these variations,each R⁹ and R¹⁰ is H. In some of these variations, each R⁷, R⁸, R⁹ andR¹⁰ is H. In some of these variations, Q is an unsubstituted pyridylgroup which may be attached to the parent structure at any position(e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl). In some of these variations,Q is 3-pyridyl or 4-pyridyl. In some of these variations, Q is pyridylsubstituted a methyl (e.g., 6-methyl-3-pyridyl and 3-methyl-4-pyridyl).In some of these variations, Q is phenyl substituted with a halo group(e.g., fluorophenyl). In some of these variations, Q is 4-fluorophenyl.In some of these variations, Q is phenyl substituted with —C(O)NR¹⁶R¹⁷,wherein each R¹⁶ and R¹⁷ is H. In some of these variations, Q is4-carbamoylphenyl.

In some variations, X is CR^(6a), wherein R^(6a) is H, halo or C₁-C₅alkyl; and each R⁶ is independently H, halo or C₁-C₅ alkyl. In othervariations, X is N. In some variations, R¹ is H or C₁-C₅ alkyl. In somevariations, R⁷ is H or C₁-C₅ alkyl, and R⁸ is H, hydroxyl, N(R¹¹)R¹² or—OC(O)C₁-C₅ alkyl. In other variations, R⁷ is H or C₁-C₅ alkyl, and R⁸is H or hydroxyl. In yet other variations, R⁷ is H or C₁-C₅ alkyl, andR⁸ is hydroxyl. In yet other variations, R⁷ is H, R⁸ is hydroxyl, n iszero and m is 1. In certain variations, R⁷ is methyl, R⁸ is hydroxyl, nis zero and m is 1.

In some variations, Q is unsubstituted pyridyl; unsubstituted pyrimidyl;unsubstituted pyrazinyl; unsubstituted phenyl; unsubstituted imidazolyl;unsubstituted triazolyl; pyridyl substituted with 1 to 3 substituentsindependently selected form the group consisting of halo, C₁-C₅ alkyl,halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷, wherein eachR¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅ alkyl;pyrimidyl substituted with 1 to 3 substituents independently selectedform the group consisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅alkyl, carboxyl and —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ isindependently H or optionally substituted C₁-C₅ alkyl; pyrazinylsubstituted with 1 to 3 substituents independently selected form thegroup consisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl,carboxyl and —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ is independently Hor optionally substituted C₁-C₅ alkyl; phenyl substituted with 1 to 3substituents independently selected form the group consisting of halo,C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷,wherein each R¹⁶ and R¹⁷ is independently H or optionally substitutedC₁-C₅ alkyl; imidazolyl substituted with 1 to 3 substituentsindependently selected form the group consisting of halo, C₁-C₅ alkyl,halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷, wherein eachR¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅ alkyl; ortriazolyl substituted with 1 to 3 substituents independently selectedform the group consisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅alkyl, carboxyl and —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ isindependently H or optionally substituted C₁-C₅ alkyl.

In certain variations, X is CR^(6a), wherein R^(6a) is H, halo or C₁-C₅alkyl; each R⁶ is independently H, halo or C₁-C₅ alkyl; R⁷ is H or C₁-C₅alkyl; R⁸ is H, hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl; each R⁹ andR¹⁰ is hydrogen; and Q is unsubstituted pyridyl; or pyridyl substitutedwith 1 to 3 substituents independently selected from the groupconsisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl, carboxyland —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ is independently H oroptionally substituted C₁-C₅ alkyl. In some variations, n is 0 and m is1; R⁷ is H or CH₃; and R⁸ is H or hydroxyl.

In yet other variations, X is N; R⁷ is H or C₁-C₅ alkyl; R⁸ is H,hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl; each R⁹ and R¹⁰ is hydrogen;and Q is unsubstituted pyridyl; or pyridyl substituted with 1 to 3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷,wherein each R¹⁶ and R¹⁷ is independently H or optionally substitutedC₁-C₅ alkyl. In some variations, n is 0 and m is 1; R⁷ is H or CH₃; andR⁸ is H or hydroxyl.

In some variations, n is 0 and m is 1; R¹ is taken together with R^(2a)to form a propylene (—CH₂CH₂CH₂—) moiety; X is CR^(6a), wherein R^(6a)is H, halo or C₁-C₅ alkyl; each R⁶ is independently H, halo or C₁-C₅alkyl; R⁷ is H or C₁-C₅ alkyl; R⁸ is H, hydroxyl, N(R¹¹)R¹² or—OC(O)C₁-C₅ alkyl; each R⁹ and R¹⁰ is hydrogen; and Q is unsubstitutedpyridyl; or pyridyl substituted with 1 to 3 substituents independentlyselected from the group consisting of halo, C₁-C₅ alkyl,halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷, wherein eachR¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅ alkyl. Insome variations, R⁷ is H or CH₃; and R⁸ is H or hydroxyl.

In some variations, the compound is Compound No. 325, 129d, 130a,II-121b, II-123b, II-127a, II-128b, II-130a, II-131, and II-6b.

In some variations, n is 0 and m is 1; each of R^(2b), R^(3b), R^(4a)and R^(4b) is H; t is 1. In certain variations, X is CH. In othervariations, X is N. In yet other variations, wherein R¹ is H or CH₃. Inyet other variations, R^(2a) is H or is taken together with R¹ to form apropylene (—CH₂CH₂CH₂—) moiety. In yet other variations, each R⁶ andR^(6a) is independently H, halo or C₁-C₅ alkyl. In yet other variations,R⁷ is H or CH₃. In one variation, R⁸ is hydroxyl. In some variations, Qis unsubstituted pyridyl; unsubstituted pyrimidyl; unsubstitutedpyrazinyl; unsubstituted phenyl; unsubstituted imidazolyl; unsubstitutedtriazolyl; pyridyl substituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃;pyrimidyl substituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃; pyrazinylsubstituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃; or phenylsubstituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃. In some variations,X is CH; each R⁶ is independently H, halo or C₁-C₅ alkyl; R⁷ is H orCH₃; R⁸ is hydroxyl; and Q is unsubstituted pyridyl, or pyridylsubstituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃. In some variations,the compound is Compound No. 325, 129d, 130a, II-121b, II-127a, II-128b,II-130a, II-131, and II-6b.

In another embodiment, the compound of formula (A-III) has the formula(A-IIIA):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H; C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl;C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl;C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl;or —C(O)O—C₁-C₅ alkyl, or is taken together with R^(2a) or R^(3a) toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halo, C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, hydroxyl, carboxyl and perhaloalkyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety,or is taken together with R⁹ to form a C₃-C₅ alkylene when R⁸ and R¹⁰are taken together to form a bond;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety, or is taken together with R¹⁰ to form a bond;

R⁹ is H or optionally substituted C₁-C₅ alkyl, or is taken together withR⁷ to form a C₃-C₅ alkylene when R⁸ and R¹⁰ are taken together to form abond;

R¹⁰ is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R⁸ to form a bond;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl, or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

Q is unsubstituted aryl; unsubstituted heteroaryl; aryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino; or heteroaryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In some variations, Q is unsubstituted aryl; unsubstituted heteroaryl;aryl substituted with halo, CH₃, CF₃, or OCH₃; or heteroaryl substitutedwith halo, CH₃, CF₃, or OCH₃. In other variations, Q is unsubstitutedpyridyl; unsubstituted pyrimidyl; unsubstituted pyrazinyl; unsubstitutedphenyl; pyridyl substituted with halo, CH₃, CF₃, or OCH₃; pyrimidylsubstituted with halo, CH₃, CF₃, or OCH₃; pyrazinyl substituted withhalo, CH₃, CF₃, or OCH₃; or phenyl substituted with halo, CH₃, CF₃, orOCH₃.

In one variation, the compound is of the formula (A-IIIA), wherein Q, X,R¹, R^(2a), R^(3a), R⁶, R^(6a), R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are asdefined for the formula (A-IIIA); R⁷ is H, halo, optionally substitutedC₁-C₅ alkyl; R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, or —OC(O)C₁-C₅ alkyl optionally substituted with amino;and each R⁹ and R¹⁰ is independently H or optionally substituted C₁-C₅alkyl.

In some variations of the compound of the formula (A-IIIA), each R^(2a)and R^(3a) is H. In some variations, R¹ is C₁-C₅ alkyl (e.g., methyl).In some variations, each R⁶ and R^(6a) is independently halo (e.g.,chloro) or C₁-C₅ alkyl (e.g., methyl). In some variations, each R⁶ andR^(6a) is independently halo (e.g., chloro or fluoro). In somevariations, each R⁶ or R^(6a) is chloro. In some variations, each R⁶ andR^(6a) is independently C₁-C₅ alkyl (e.g., methyl). In some variations,X is CR^(6a), wherein R^(6a) is H or halo. In some variations, X isCR^(6a), wherein R^(6a) is H. In some variations, X is CR^(6a), whereinR^(6a) is chloro. In some variations, X is CR^(6a), wherein R^(6a) ishalo (e.g., chloro or fluoro). In some variations, R⁶ is H or halo. Insome variations, R⁶ is H. In some variations, R⁶ is chloro. In somevariations, R⁶ is halo (e.g., chloro or fluoro). In some variations, R⁷is H or C₁-C₅ alkyl (e.g., methyl). In some variations, X is N. In somevariations, R⁷ is H. In some variations, R⁷ is C₁-C₅ alkyl (e.g.,methyl). In some variations, R⁸ is H, hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅alkyl. In some variations, R⁸ is H or hydroxyl. In some variations, R⁸is N(R¹¹)R¹² where each R¹¹ and R¹² is H. In some variations, R⁸ is—OC(O)C₁-C₅ alkyl (e.g., —OC(O)-t-butyl). In some variations, R⁷ is H orC₁-C₅ alkyl (e.g., methyl) and R⁸ is H, hydroxyl, N(R¹¹)R¹² or—OC(O)C₁-C₅ alkyl. In some variations, R⁷ is H; and R⁸ is H, hydroxyl,N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl. In some variations, R⁷ is C₁-C₅ alkyl(e.g., methyl); and R⁸ is H, hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl.In some variations, R⁷ is H or C₁-C₅ alkyl (e.g., methyl); and R⁸ is Hor hydroxyl. In some variations, R⁷ is H or C₁-C₅ alkyl (e.g., methyl);and R⁸ is H or hydroxyl. In some variations, R⁷ is H; and R⁸ ishydroxyl. In some variations, R⁷ is methyl; and R⁸ is hydroxyl. In somevariations, R⁷ is H; and R⁸ is N(R¹¹)R¹², wherein each R¹¹ and R¹² is H.In some variations, R⁷ is H; and R⁸ is —OC(O)C₁-C₅ alkyl (e.g.,—OC(O)-t-butyl). In some variations, R⁹ is H or C₁-C₅ alkyl (e.g.,methyl). In some variations, R¹⁰ is H or C₁-C₅ alkyl (e.g., methyl). Insome variations, each R⁹ and R¹⁰ is H. In some variations, one of R⁹ andR¹⁰ is H and the other of R⁹ and R¹⁰ is C₁-C₅ alkyl (e.g., methyl). Insome variations, Q is an unsubstituted heteroaryl (e.g., pyridyl). Insome variations, Q is an unsubstituted pyridyl group which may beattached to the parent structure at any position (e.g., 2-pyridyl,3-pyridyl or 4-pyridyl). In some variations, Q is 3-pyridyl or4-pyridyl. In some variations, Q is heteroaryl substituted with asubstituent selected form the group consisting of halo (e.g., fluoro orchloro), C₁-C₅ alkyl (e.g., methyl), halo-substituted C₁-C₅ alkyl (e.g.,CF₃) and carboxyl. In some variations, Q is heteroaryl substituted withhalo (e.g., fluoro or chloro) or C₁-C₅ alkyl (e.g., methyl). In somevariations, Q is heteroaryl substituted with C₁-C₅ alkyl (e.g., methyl).In some variations, Q is a pyridyl optionally substituted with a methylwhere the pyridyl group may be attached to the parent structure at anyposition and the methyl group may be attached to the pyridyl group atany open position (e.g., 6-methyl-3-pyridyl and 3-methyl-4-pyridyl). Insome variations, Q is phenyl substituted with a substituent selectedform the group consisting of halo (e.g., fluoro or chloro), C₁-C₅ alkyl(e.g., methyl), halo-substituted C₁-C₅ alkyl (e.g., CF₃), carboxyl and—C(O)NR¹⁶R¹⁷ where each R¹⁶ and R¹⁷ is independently H or optionallysubstituted C₁-C₅ alkyl. In some variations, Q is phenyl substitutedwith a halo group (e.g., fluorophenyl). In some variations, Q is4-fluorophenyl. In some variations, Q is phenyl substituted with—C(O)NR¹⁶R¹⁷ where each R¹⁶ and R¹⁷ is H.

In some variations of the compound of the formula (A-IIIA), R¹ is C₁-C₅alkyl (e.g., methyl), each R^(2a) and R^(3a) is H, R⁶ is methyl orchloro, and X is CH. In some of these variations, R⁷ is H or C₁-C₅ alkyl(e.g., methyl) and R⁸ is hydroxyl. In some of these variations, R⁷ is Hand R⁸ is hydroxyl. In some of these variations, R⁷ is methyl and R⁸ ishydroxyl. In some of these variations, R⁹ is H or C₁-C₅ alkyl (e.g.,methyl) and R¹⁰ is H. In some of these variations, each R⁹ and R¹⁰ is H.In some of these variations, R⁷ is H or C₁-C₅ alkyl (e.g., methyl), R⁸is hydroxyl, and each R⁹ and R¹⁰ is H. In some of these variations, Q isan unsubstituted pyridyl group which may be attached to the parentstructure at any position (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl). Insome of these variations, Q is 3-pyridyl or 4-pyridyl. In some of thesevariations, Q is pyridyl substituted a methyl (e.g., 6-methyl-3-pyridyland 3-methyl-4-pyridyl). In some of these variations, phenyl substitutedwith a halo group (e.g., fluorophenyl). In some of these variations, Qis 4-fluorophenyl. In some of these variations, Q is phenyl substitutedwith —C(O)NR¹⁶R¹⁷ where each R¹⁶ and R¹⁷ is H. In some of thesevariations, Q is 4-carbamoylphenyl.

In some variations of the compound of the formula (A-IIIA), R¹ is C₁-C₅alkyl (e.g., methyl), each R^(2a) and R^(3a) is H, R⁶ is methyl orchloro, and X is CH. In some variations, R⁷ is H and R⁸ is N(R¹¹)R¹²,wherein each R¹¹ and R¹² is H. In some variations, R⁷ is H and R⁸ is—OC(O)C₁-C₅ alkyl (e.g., —OC(O)-t-butyl). In some of these variations,R⁹ is H or C₁-C₅ alkyl (e.g., methyl); and R¹⁰ is H. In some of thesevariations, each R⁹ and R¹⁰ is H. In some of these variations, R⁷ is H,R⁸ is NH₂, and each R⁹ and R¹⁰ is H. In some of these variations, Q isan unsubstituted pyridyl group which may be attached to the parentstructure at any position (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl). Insome of these variations, Q is 3-pyridyl or 4-pyridyl. In some of thesevariations, Q is pyridyl substituted a methyl (e.g., 6-methyl-3-pyridyland 3-methyl-4-pyridyl). In some of these variations, Q is phenylsubstituted with a halo group (e.g., fluorophenyl). In some of thesevariations, Q is 4-fluorophenyl. In some of these variations, Q isphenyl substituted with —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ is H. Insome of these variations, Q is 4-carbamoylphenyl.

In some variations of the compound of the formula (A-IIIA), R¹ andR^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety andR^(3a) is H. In some of these variations, X is N. In some of thesevariations, X is CH. In some of these variations, R⁶ is C₁-C₅ alkyl(e.g., methyl) or halo (e.g., chloro). In some of these variations, R⁶is methyl or chloro. In some of these variations, R⁷ is H or C₁-C₅ alkyl(e.g., methyl) and R⁸ is H or hydroxyl. In some of these variations, R⁷is H and R⁸ is hydroxyl. In some of these variations, R⁷ is methyl andR⁸ is hydroxyl. In some of these variations, each R⁷ and R⁸ is H. Insome of these variations, R⁹ is H or C₁-C₅ alkyl (e.g., methyl) and R¹⁰is H. In some of these variations, each R⁹ and R¹⁰ is H. In some ofthese variations, R⁷ is H or C₁-C₅ alkyl (e.g., methyl), R⁸ is H orhydroxyl, and each R⁹ and R¹⁰ is H. In some of these variations, eachR⁷, R⁸, R⁹ and R¹⁰ is H. In some of these variations, Q is anunsubstituted pyridyl group which may be attached to the parentstructure at any position (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl). Insome of these variations, Q is 3-pyridyl or 4-pyridyl. In some of thesevariations, Q is pyridyl substituted a methyl (e.g., 6-methyl-3-pyridyland 3-methyl-4-pyridyl). In some of these variations, Q is phenylsubstituted with a halo group (e.g., fluorophenyl). In some of thesevariations, Q is 4-fluorophenyl. In some of these variations, Q isphenyl substituted with —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ is H. Insome of these variations, Q is 4-carbamoylphenyl.

In another embodiment, the compound of formula (A-III) has the formula(A-IIIB):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1-3 substituents independentlyselected from halo, hydroxyl, carboxyl and perhaloalkyl, or —C(O)O—C₁-C₅alkyl, or is taken together with R^(2a) or R^(3a) to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halo, C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, hydroxyl, carboxyl and perhaloalkyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety,or is taken together with R⁹ to form a C₃-C₅ alkylene when R⁸ and R¹⁰are taken together to form a bond;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety, or is taken together with R¹⁰ to form a bond;

R⁹ is H or optionally substituted C₁-C₅ alkyl, or is taken together withR⁷ to form a C₃-C₅ alkylene when R⁸ and R¹⁰ are taken together to form abond;

R¹⁰ is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R⁸ to form a bond;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl, or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

Q is unsubstituted aryl; unsubstituted heteroaryl; aryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino; or heteroaryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In some variations, Q is unsubstituted aryl; unsubstituted heteroaryl;aryl substituted with halo, CH₃, CF₃, or OCH₃; or heteroaryl substitutedwith halo, CH₃, CF₃, or OCH₃. In other variations, Q is unsubstitutedpyridyl; unsubstituted pyrimidyl; unsubstituted pyrazinyl; unsubstitutedphenyl; pyridyl substituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃;pyrimidyl substituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃; pyrazinylsubstituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃; or phenylsubstituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃.

In some variations of the compound of the formula (A-IIIB), R¹ is C₁-C₅alkyl (e.g., methyl), each R^(2a) and R^(3a) is H, R⁶ is methyl orchloro, and X is CH. In some of these variations, R⁷ is H or C₁-C₅ alkyl(e.g., methyl) and R⁸ is hydroxyl. In some of these variations, R⁷ is Hand R⁸ is hydroxyl. In some of these variations, R⁷ is methyl and R⁸ ishydroxyl. In some of these variations, R⁹ is H or C₁-C₅ alkyl (e.g.,methyl) and R¹⁰ is H. In some of these variations, each R⁹ and R¹⁰ is H.In some of these variations, R⁷ is H or C₁-C₅ alkyl (e.g., methyl), R⁸is hydroxyl, and each R⁹ and R¹⁰ is H. In some of these variations, Q isan unsubstituted pyridyl group which may be attached to the parentstructure at any position (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl). Insome of these variations, Q is 3-pyridyl or 4-pyridyl. In some of thesevariations, Q is pyridyl substituted a methyl (e.g., 6-methyl-3-pyridyland 3-methyl-4-pyridyl). In some of these variations, Q is phenylsubstituted with a halo group (e.g., fluorophenyl). In some of thesevariations, Q is 4-fluorophenyl.

In another embodiment, the compound of formula (A-III) has the formula(A-IIIC):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1-3 substituents selected fromhalo, hydroxyl, carboxyl and perhaloalkyl, or —C(O)O—C₁-C₅ alkyl, or istaken together with R^(2a) or R^(3a) to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(5a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halo, C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, hydroxyl, carboxyl and perhaloalkyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety,or is taken together with R⁹ to form a C₃-C₅ alkylene when R⁸ and R¹⁰are taken together to form a bond;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety, or is taken together with R¹⁰ to form a bond;

R⁹ is H or optionally substituted C₁-C₅ alkyl, or is taken together withR⁷ to form a C₃-C₅ alkylene when R⁸ and R¹⁰ are taken together to form abond;

R¹⁰ is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R⁸ to form a bond;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl, or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

Q is unsubstituted aryl; unsubstituted heteroaryl; aryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino; or heteroaryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In some variations, Q is unsubstituted aryl; unsubstituted heteroaryl;aryl substituted with halo, CH₃, CF₃, or OCH₃; or heteroaryl substitutedwith halo, CH₃, CF₃, or OCH₃. In other variations, Q is unsubstitutedpyridyl; unsubstituted pyrimidyl; unsubstituted pyrazinyl; unsubstitutedphenyl; pyridyl substituted with halo, CH₃, CF₃, or OCH₃; pyrimidylsubstituted with halo, CH₃, CF₃, or OCH₃; pyrazinyl substituted withhalo, CH₃, CF₃, or OCH₃; or phenyl substituted with halo, CH₃, CF₃, orOCH₃.

In one variation, the compound is of the formula (A-IIIC), wherein Q, X,R¹, R^(2a), R^(3a), R^(5a), R⁶, R^(6a), R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ areas defined for the formula (A-IIIC), R⁷ is H, halo, optionallysubstituted C₁-C₅ alkyl, R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³,S(O)R¹³, SO₂R¹³, —OC(O)N(R¹⁴)R¹⁵, or —OC(O)C₁-C₅ alkyl optionallysubstituted with amino, and each R⁹ and R¹⁰ is independently H oroptionally substituted C₁-C₅ alkyl; or a salt, solvate or N-oxidethereof.

In another embodiment, the compound of formula (A-III) has the formula(A-IIID):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl, or is taken together with R^(2a) or R^(3a) toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halo, C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, hydroxyl, carboxyl and perhaloalkyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety,or is taken together with R⁹ to form a C₃-C₅ alkylene when R⁸ and R¹⁰are taken together to form a bond;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety, or is taken together with R¹⁰ to form a bond;

R⁹ is H or optionally substituted C₁-C₅ alkyl, or is taken together withR⁷ to form a C₃-C₅ alkylene when R⁸ and R¹⁰ are taken together to form abond;

R¹⁰ is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R⁸ to form a bond;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl, or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

Q is unsubstituted aryl; unsubstituted heteroaryl; aryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino; or heteroaryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In some variations, Q is unsubstituted aryl; unsubstituted heteroaryl;aryl substituted with halo, CH₃, CF₃, or OCH₃; or heteroaryl substitutedwith halo, CH₃, CF₃, or OCH₃. In other variations, Q is unsubstitutedpyridyl; unsubstituted pyrimidyl; unsubstituted pyrazinyl; unsubstitutedphenyl; pyridyl substituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃;pyrimidyl substituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃; pyrazinylsubstituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃; or phenylsubstituted with halo, CH₃, CF₃, CONH₂, OH, or OCH₃.

In one variation, the compound is of the formula (A-IIID), wherein Q, X,R¹, R^(2a), R^(3a), R⁶, R^(6a), R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ are asdefined for the formula (A-IIID), R⁷ is H, halo, optionally substitutedC₁-C₅ alkyl, R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, or —OC(O)C₁-C₅ alkyl optionally substituted with amino,and each R⁹ and R¹⁰ is independently H or optionally substituted C₁-C₅alkyl; or a salt, solvate or N-oxide thereof.

In some variations of the compound of the formula (A-IIID), R¹ is C₁-C₅alkyl (e.g., methyl), each R^(2a) and R^(3a) is H, R⁶ is methyl orchloro, and X is CH. In some of these variations, R⁷ is H or C₁-C₅ alkyl(e.g., methyl) and R⁸ is H or hydroxyl. In some of these variations, R⁷is H and R⁸ is hydroxyl. In some of these variations, R⁷ is methyl andR⁸ is hydroxyl. In some of these variations, R⁹ is H or C₁-C₅ alkyl(e.g., methyl) and R¹⁰ is H. In some of these variations, each R⁹ andR¹⁰ is H. In some of these variations, R⁷ is H or C₁-C₅ alkyl (e.g.,methyl), R⁸ is hydroxyl, and each R⁹ and R¹⁰ is H. In some of thesevariations, Q is an unsubstituted pyridyl group which may be attached tothe parent structure at any position (e.g., 2-pyridyl, 3-pyridyl or4-pyridyl). In some of these variations, Q is 3-pyridyl or 4-pyridyl. Insome of these variations, Q is pyridyl substituted a methyl (e.g.,6-methyl-3-pyridyl and 3-methyl-4-pyridyl). In some of these variations,Q is phenyl substituted with a halo group (e.g., fluorophenyl). In someof these variations, Q is 4-fluorophenyl.

In certain embodiments, with respect to the compounds of formula (IIID),X is CH, R⁷ is H or methyl, R⁸ is H or OH, Q is phenyl, unsubstituted orsubstituted with F, Cl, or methoxy; and R⁶ is other than methyl orchloro.

In another embodiment, the compound of formula (A-III) has the formula(A-IIIE):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H; C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl;C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl;C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl; or is taken together with R^(2a) or R^(3a) toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(2a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedalkenyl; or optionally substituted aryl; or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(3a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedalkenyl; or optionally substituted aryl; or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

each R^(2b) and R^(3b) is independently H or optionally substitutedC₁-C₅ alkyl;

R⁶ is H; hydroxyl; halo; C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl; optionally substituted C₁-C₅ alkoxy or optionallysubstituted —C(O)C₁-C₅ alkyl;

R⁷ is H; halo; optionally substituted C₁-C₅ alkyl; or optionallysubstituted aryl; or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H; halo; hydroxyl; N(R¹¹)R¹²; SR¹³; S(O)R¹³, SO₂R¹³;—OC(O)N(R¹⁴)R¹⁵; —OC(O)-aryl; —OC(O)-heteroaryl; or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

Q is unsubstituted aryl; unsubstituted heteroaryl; aryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino; or heteroaryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In some variations of the compound of formula (A-IIIE), R¹ is C₁-C₅alkyl optionally substituted with 1 to 3 substituents independentlyselected from halo, hydroxyl, carboxyl and perhaloalkyl. In certainvariations, R¹ is C₁-C₅ alkyl substituted with a hydroxyl. In othervariations, R¹ is methyl. In yet other variations, R¹ is H.

In some variations of the compound of formula (A-IIIE), R⁶ is halo,C₁-C₅ alkyl, or perhaloalkyl. In certain variations, R⁶ is methyl orisopropyl. In other variations of the compound of formula (A-IIIE), eachR^(2a), R^(2b), R^(3a) and R^(3b) is H. In yet other variations of thecompound of formula (A-IIIE), R⁷ is an optionally substituted H or anunsubstituted C₁-C₅ alkyl, and R⁸ is hydroxyl. In certain variations, R⁷is methyl, and R⁸ is hydroxyl.

In yet other variations of the compound of formula (A-IIIE), Q iscycloalkyl optionally substituted with 1 to 3 substituents independentlyselected from the group consisting of halo, C₁-C₅ alkyl, C₃-C₈cycloalkyl, halo-substituted C₁-C₅ alkyl, halo-substituted C₃-C₈cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy, cyano, carboxyl, aminoacyland acylamino; aryl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, C₁-C₅ alkyl,C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl, halo-substituted C₃-C₈cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy, cyano, carboxyl, aminoacyland acylamino; or heteroaryl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino. In other variations, Q is anoptionally substituted pyridyl, an optionally substituted pyrimidyl, anoptionally substituted pyrazinyl, or an optionally substituted phenyl,wherein each of the pyridyl, pyrimidyl, pryazinyl and phenyl isindependently unsubstituted or substituted with 1 to 3 substituentsindependently selected from halo, carboxyl, alkoxy and C₁-C₅ alkyl. Inone variation, Q is an unsubstituted pyridyl. In another variation, Q isan unsubstituted pyrimidyl. In yet another variation, Q is anunsubstituted pyrazinyl. In yet another variation, Q is an unsubstitutedphenyl. In yet another variation, Q is a phenyl substituted with 1 to 3substituents independently selected from the group consisting of halo orC₁-C₅ alkyl. In one variation, Q is fluoro-phenyl.

In another embodiment, the compound is of the formula (A-IIIE-1),(A-IIIE-2), (A-IIIE-3) or (A-IIIE-4):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl;

R⁶ is H, hydroxyl, halo, C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, optionally substituted C₁-C₅ alkoxy or optionallysubstituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

each Y¹, Y², Y³, Y⁴ and Y⁵ is independently N or CR⁴ such that no morethan two of Y¹, Y², Y³, Y⁴ and Y⁵ are N, wherein R⁴ is H, halo, CH₃,CF₃, or OCH₃.

In some variations of the compound of the formula (A-IIIE-1),(A-IIIE-2), (A-IIIE-3) or (A-IIIE-4), one of Y¹, Y², Y³, Y⁴ and Y⁵ is Nand the other four of Y¹, Y², Y³, Y⁴ and Y⁵ are independently CR⁴, andwherein R⁴ is H, halo, CH₃, CF₃, or OCH₃. In other variations, Y⁵ is CH,and each Y¹, Y², Y³ and Y⁴ is independently N or CR⁴ such that two ofY¹, Y², Y³ and Y⁴ are N, and wherein R⁴ is H, halo, CH₃, CF₃, or OCH₃.In some variations, R⁴ is halo. In other variations, R⁴ is CH₃. In oneembodiment, R⁴ is F. In another embodiment, R⁴ is Cl. In someembodiments, any two of Y¹, Y², Y³, Y⁴ and Y⁵ are CR⁴, and each R⁴ isindependently Cl or F. In one embodiment, each R⁴ is Cl. In anotherembodiment, each R⁴ is F.

In some embodiments, the compound is of formula (A-IIIE-1), when each R⁷and R⁸ is H; R¹ is H or methyl; R⁶ is methyl or chloro; each Y¹, Y², Y⁴and Y⁵ is CR⁴, and Y³ is CH, CF, or CCl; then at least one of Y¹, Y², Y⁴and Y⁵ is other than CH.

In certain embodiments, with respect to the compounds of formula(A-IIIE-1), the compound is Compound No. 214.

In some embodiments, the compound is of formula (A-IIIE-2). In somevariations, X is CH. In other variations, R¹ is H or CH₃. In yet othervariations, R⁷ is H or CH₃. In yet other variations, R⁸ is hydroxyl. Insome variations, one of Y¹, Y², Y³, Y⁴ and Y⁵ is N, and the other fourof Y¹, Y², Y³, Y⁴ and Y⁵ are independently CR⁴ (e.g., optionallysubstituted pyridyl). In other variations, two of Y¹, Y², Y³, Y⁴ and Y⁵is N, and the other three of Y¹, Y², Y³, Y⁴ and Y⁵ are independently CR⁴(e.g., optionally substituted pyrimidyl or optionally substitutedpyrazinyl). In yet other variations, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴(e.g., optionally substituted phenyl). In certain variations, R⁴ is H,halo, CH₃, CF₃, or OCH₃. In one embodiment, R⁴ is F. In anotherembodiment, R⁴ is Cl. In some embodiments, any two of Y¹, Y², Y³, Y⁴ andY⁵ are CR⁴, wherein each R⁴ is independently Cl or F. In one embodiment,each R⁴ is Cl. In another embodiment, each R⁴ is F.

In some embodiments, the compound is of formula (A-IIIE-2), R⁷ isoptionally substituted cycloalkyl, R⁸ is OH, R¹ is methyl, R⁶ is methylor chloro, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴ wherein at least one R⁴ isother than H or fluoro. In another embodiment, one of Y¹, Y², Y³, Y⁴ andY⁵ is N and the rest are independently CR⁴, wherein at least one R⁴ isother than H.

In some embodiments, the compound is of formula (A-IIIE-2), R⁷ is C₁-C₅alkyl, substituted with acylamino, R⁸ is CH₂—CON(H)CH₃, R¹ is methyl orethyl, R⁶ is methyl or chloro, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴,wherein at least one R⁴ is other than H, fluoro, chloro, methoxy, ordifluoro. In another embodiment, one of Y¹, Y², Y³, Y⁴ and Y⁵ is N andthe rest are independently CR⁴, wherein at least one R⁴ is other than Hor methyl. In another embodiment, two of Y¹, Y², Y³, Y⁴ and Y⁵ are N andthe rest are independently CR⁴, wherein at least one R⁴ is other than H.

In some embodiments, the compound is of formula (A-IIIE-2), R⁷ is C₁-C₅alkyl, substituted with —C(O)OR^(7a), R^(7a) is H or optionallysubstituted C₁-C₅ alkyl, R¹ is methyl or ethyl, R⁶ is methyl or chloro,each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴, wherein at least one R⁴ is other thanH, fluoro, chloro, methoxy, or difluoro. In another embodiment, one ofY¹, Y², Y³, Y⁴ and Y⁵ is N and the rest are independently CR⁴, whereinat least one R⁴ is other than H, or methyl. In another embodiment, twoof Y¹, Y², Y³, Y⁴ and Y⁵ are N and the rest are independently CR⁴,wherein at least one R⁴ is other than H.

In some embodiments, the compound is of formula (A-IIIE-2), R⁷ is C₁-C₅alkyl, substituted with 1-3 halo, R⁷ is CF₃, R⁸ is OH, R¹ is methyl, R⁶is methyl, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴, wherein at least one R⁴ isother than H or fluoro.

In some embodiments, the compound is of formula (A-IIIE-2), R⁷ isoptionally substituted phenyl, R⁸ is OH, R¹ is methyl or ethyl, R⁶ ismethyl or chloro, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴, wherein at leastone R⁴ is other than H, or fluoro. In another embodiment, one of Y¹, Y²,Y³, Y⁴ and Y⁵ is N and the rest are independently CR⁴, wherein at leastone R⁴ is other than H.

In some embodiments, the compound is of formula (A-IIIE-2), R⁸ is halo.In one embodiment, R⁸ is fluoro or chloro, R¹ is methyl, ethyl,isopropyl, or cyclopropyl, R⁶ is methyl or chloro, each Y¹, Y², Y³, Y⁴and Y⁵ is CR⁴, wherein at least one R⁴ is other than H, fluoro, chloro,methoxy, or difluoro. In another embodiment, one of Y¹, Y², Y³, Y⁴ andY⁵ is N and the rest are independently CR⁴, wherein at least one R⁴ isother than H, or methyl. In another embodiment, two of Y¹, Y², Y³, Y⁴and Y⁵ are N and the rest are independently CR⁴, wherein at least one R⁴is other than H.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), each R⁷ and R⁸ is H, and the compound is Compound No. 60,61, 84-86, 89, 91, 117, 180, 184, 200, 201, 202, 204, 206-210, 213,217-19, 297-299, 317, 319-320, or 332.

In certain embodiments, with respect to the compounds of formula (I),each R⁷ and R⁸ is H, and the compound is Compound No. II-39 or II-40.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is H, R⁸ is OH, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴, andthe compound is Compound No. 30, 52, 66, 67, 139, 142, 183, or 203.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is H, R⁸ is OH, each Y, Y¹, Y³, Y⁴ and Y⁵ is CR⁴, and thecompound is Compound No. II-88 or II-192.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is H, R⁸ is OH, each Y¹, Y³, Y⁴ and Y⁵ is CR⁴, Y² is N,and the compound is Compound No. 7, 21, 51, 59, 62, 140, or 144.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is H, R⁸ is OH, each Y¹, Y³, Y⁴ and Y⁵ is CR⁴, Y² is N,and the compound is Compound No. II-57, II-92, II-94, II-190 or II-191.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is H, R⁸ is OH, each Y¹, Y³, Y⁴ and Y⁵ is CR⁴, Y² is N,and the compound is Compound No. III-1.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is H, R⁸ is OH, each Y¹, Y², Y⁴ and Y⁵ is CR⁴, Y³ is N,and the compound is Compound No. 3, 4, 6, 11, 23, 49, 63, 69-72, 81,133, or 135.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is H, R⁸ is OH, each Y¹, Y², Y³ and Y⁵ is CR⁴, Y² is N,and the compound is Compound No. II-60, II-63, II-64, II-65, II-67,II-68, II-75, II-83, II-84, II-90, II-93, or II-97.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is methyl, R⁸ is OH, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴,and the compound is Compound No. 90, 98, or 254.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is methyl, R⁸ is OH, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴,and the compound is Compound No. II-36, 47, 163, 189, 194 to 203, orII-205.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is methyl, R⁸ is OH, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴,and the compound is Compound No. III-36, III-47, III-50, or III-51.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is methyl, R⁸ is OH, each Y¹, Y², Y⁴ and Y⁵ is CR⁴, Y³ isN, and the compound is Compound No. 1, 2, or 253.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is methyl, R⁸ is OH, each Y¹, Y², Y⁴ and Y⁵ is CR⁴, Y³ isN, and the compound is Compound No. II-58, II-168, II-172, II-173,II-181, II-182, or III-49.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is methyl, R⁸ is OH, each Y¹, Y³, Y⁴ and Y⁵ is CR⁴, Y² isN, and the compound is Compound No. 5, 29, 31, 56, 64, 93, 143, 169,174, or 179.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is methyl, R⁸ is OH, each Y¹, Y³, Y⁴ and Y⁵ is CR⁴, Y² isN, and the compound is Compound No. II-80, 105, 118, 123, 124, 136, 141,145, 148, 154, 193, 220, 269, II-280, or III-48.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁸ is N(R¹¹)R¹², and the compound is Compound No. 27, 149 to152, or 157.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁸ is N(R¹¹)R¹², and the compound is Compound No. II-1, II-8to II-14, or II-260.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is other than H or methyl, R⁸ is OH, and the compound isCompound No. 33 to 35, 223, or 263.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is other than H or methyl, R⁸ is OH, and the compound isCompound No. II-160, II-162, II-166, II-167, II-174, II-186, II-206,II-255, II-257, II-259, II-264, II-265, II-278, or III-52.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is methyl, R⁸ is H, and the compound is Compound No. 255,288, or 289.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), R⁷ is substituted C₁-C₅ alkyl, R⁸ is H, and the compound isCompound No. II-216 to II-218, II-221 to II-231, II-232, or III-224 toIII-253.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), the compound is Compound No. 25, 54, 68, 83, 94, 102, 130,141, 146, 147, 260, or 338.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), the compound is Compound No. II-15, II-16, II-19,II-207-II-213, II-256, II-258, II-262, II-263, II-274, II-277, II-295,II-296, II-299, or V-14.

In some embodiments, the compound is of formula (A-IIIE-3), when each R⁷and R⁸ is H; R¹ is methyl; R⁶ is chloro; each Y¹, Y², Y⁴ and Y⁵ is CR⁴,and Y³ is CH, CF, or CCl; then at least one of Y¹, Y², Y⁴ and Y⁵ isother than CH.

In certain embodiments, with respect to the compounds of formula(A-IIIE-3), the compound is Compound No. 40, 53, 65, 119, 215, 315,II-169, or II-184.

In some embodiments, the compound is of formula (A-IIIE-4), when each R⁷and R⁸ is H, or R⁷ taken together with R⁸ form a —CH₂ moiety, R¹ ismethyl; R⁶ is F, Cl, CF₃, ethenyl, or propenyl; each Y¹, Y², Y⁴ and Y⁵is CR⁴, and Y³ is CH, CF or CCl; then at least one of Y¹, Y², Y⁴ and Y⁵is other than CH.

In certain embodiments, with respect to the compounds of formula(A-IIIE-4), the compound is Compound No. 32, 44, 45, 48, 57, 82, 216,II-170, or II-183.

In another embodiment, the compound is of the formula (A-IIIE-5),(A-IIIE-6), (A-IIIE-7) or (A-IIIE-8):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl;

R⁶ is H, hydroxyl, halo, C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, optionally substituted C₁-C₅ alkoxy or optionallysubstituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety, or is taken together with R¹⁰ to form a bond;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene;

Q is

wherein

-   -   each Z¹, Z², Z³ and Z⁴ is independently N or CR⁴ such that no        more than two of Z¹, Z², Z³ and Z⁴ are N, wherein R⁴ is H, halo,        CH₃, CF₃, or OCH₃;    -   each Z⁵ and Z¹⁰ is independently O, S or NR^(4a), wherein R^(4a)        is H or CH₃; and    -   each Z⁶, Z⁷, Z⁸, Z⁹, Z¹¹ and Z¹² is independently N or CR⁴,        wherein R⁴ is H, halo, CH₃, CF₃, or OCH₃.

In other embodiments, the compound is of formula (A-IIIE-6). In othervariations, R¹ is H or CH₃. In yet other variations, R⁷ is H or CH₃. Inyet other variations, R⁸ is hydroxyl.

In some variations, Q is

In some variations, R⁴ is H, halo, CH₃, CF₃, or OCH₃.

In some variations of the compound of formula (A-IIIE-1), (A-IIIE-2),(A-IIIE-3), (A-IIIE-4), (A-IIIE-5), (A-IIIE-6), (A-IIIE-7) or(A-IIIE-8), R¹ is C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl. In certain variations, R¹ is C₁-C₅ alkyl substituted witha hydroxyl. In other variations, R¹ is methyl. In some variations, R⁶ ishalo, C₁-C₅ alkyl or perhaloalkyl. In certain variations, R⁶ is methylor isopropyl. In yet other variations of the compound of formula(A-IIIE-1), (A-IIIE-2), (A-IIIE-3), (A-IIIE-4), (A-IIIE-5), (A-IIIE-6),(A-IIIE-7) or (A-IIIE-8), R⁷ is an optionally substituted or anunsubstituted C₁-C₅ alkyl, and R⁸ is hydroxyl. In certain variations, R⁷is methyl, and R⁸ is hydroxyl.

In some embodiments, the compound is of formula (A-IIIE-6), when each R⁷and R⁸ is H, R⁶ is H, methyl, Cl, F, CF₃, or methoxy; then R¹ is otherthan methyl or cyclopropyl.

In certain embodiments, with respect to the compounds of formula(A-IIIE-6), the compound is Compound No. 131, 307, 308, 318, 326,II-106, or II-142.

In another embodiment, the compound is of the formula (A-IIIF):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl, or is taken together with R^(2a) or R^(3a) toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

each R^(2b) and R^(3b) is independently H or optionally substitutedC₁-C₅ alkyl;

R⁶ is H, hydroxyl, halo, C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, optionally substituted C₁-C₅ alkoxy or optionallysubstituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

Q is unsubstituted aryl; unsubstituted heteroaryl; aryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino; or heteroaryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In another embodiment, the compound is of the formula (A-IIIF-1),(A-IIIF-2), (A-IIIF-3) or (A-IIIF-4):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl;

R⁶ is H, hydroxyl, halo, C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, optionally substituted C₁-C₅ alkoxy or optionallysubstituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

each Y¹, Y², Y³, Y⁴ and Y⁵ is independently N or CR⁴ such that no morethan two of Y¹, Y², Y³, Y⁴ and Y⁵ are N, wherein R⁴ is H, halo, CH₃,CF₃, or OCH₃.

In some variations, one of Y¹, Y², Y³, Y⁴ and Y⁵ is N and the other fourof Y¹, Y², Y³, Y⁴ and Y⁵ are independently CR⁴, and wherein R⁴ is H,halo, CH₃, CF₃, or OCH₃. In other variations, Y⁵ is CH, and each Y¹, Y²,Y³ and Y⁴ is independently N or CR⁴ such that two of Y¹, Y², Y³ and Y⁴are N, and wherein R⁴ is H, halo, CH₃, CF₃, or OCH₃. In some variations,R⁴ is halo. In other variations, R⁴ is CH₃. In one embodiment, R⁴ is F.In another embodiment, R⁴ is Cl. In some embodiments, any two of Y¹, Y²,Y³, Y⁴ and Y⁵ are CR⁴, and each R⁴ is independently Cl or F. In oneembodiment, each R⁴ is Cl. In another embodiment, each R⁴ is F.

In some embodiments, the compound is of formula (A-IIIF-1), when R⁷ ismethyl, R⁸ is OH, R¹ is methyl, R⁶ is chloro; then Y³ is other than N.

In some embodiments, the compound is of formula (A-IIIF-2), when eachY¹, Y², Y³, Y⁴ and Y⁵ is independently CR⁴; and R¹ is methyl, ethyl,iso-propyl, or cyclopropyl; then R⁶ is other than Cl or methyl.

In some embodiments, the compound is of formula (A-IIIF-2), R⁷ isoptionally substituted cycloalkyl, R⁸ is OH, R¹ is methyl, R⁶ is methylor chloro, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴, wherein at least one R⁴ isother than H or fluoro. In another embodiment, one of Y¹, Y², Y³, Y⁴ andY⁵ is N and the rest are independently CR⁴, wherein at least one R⁴ isother than H.

In some embodiments, the compound is of formula (A-IIIF-2), R⁷ is C₁-C₅alkyl, substituted with acylamino, R⁸ is CH₂—CON(H)CH₃, R¹ is methyl orethyl, R⁶ is methyl or chloro, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴,wherein at least one R⁴ is other than H, fluoro, chloro, methoxy, ordifluoro. In another embodiment, one of Y¹, Y², Y³, Y⁴ and Y⁵ is N andthe rest are independently CR⁴, wherein at least one R⁴ is other than H,or methyl. In another embodiment, two of Y¹, Y², Y³, Y⁴ and Y⁵ are N andthe rest are independently CR⁴, wherein at least one R⁴ is other than H.

In some embodiments, the compound is of formula (A-IIIF-2), R⁷ is C₁-C₅alkyl, substituted with —C(O)OR^(7a), R^(7a) is H or optionallysubstituted C₁-C₅ alkyl, R¹ is methyl or ethyl, R⁶ is methyl or chloro,each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴, wherein at least one R⁴ is other thanH, fluoro, chloro, methoxy, or difluoro. In another embodiment, one ofY¹, Y², Y³, Y⁴ and Y⁵ is N and the rest are independently CR⁴, whereinat least one R⁴ is other than H, or methyl. In another embodiment, twoof Y¹, Y², Y³, Y⁴ and Y⁵ are N and the rest are independently CR⁴,wherein at least one R⁴ is other than H.

In some embodiments, the compound is of formula (A-IIIF-2), R⁷ is C₁-C₅alkyl, substituted with 1-3 halo, R⁷ is CF₃, R⁸ is OH, R⁷ is methyl, R⁶is methyl, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴, wherein at least one R⁴ isother than H or fluoro.

In some embodiments, the compound is of formula (A-IIIF-2), R⁷ isoptionally substituted phenyl, R⁸ is OH, R¹ is methyl or ethyl, R⁶ ismethyl or chloro, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴, wherein at leastone R⁴ is other than H, or fluoro. In another embodiment, one of Y¹, Y²,Y³, Y⁴ and Y⁵ is N and the rest are independently CR⁴, wherein at leastone R⁴ is other than H.

In some embodiments, the compound is of formula (A-IIIF-2), and R⁸ ishalo. In one embodiment, R⁸ is fluoro or chloro, R¹ is methyl, ethyl,isopropyl, or cyclopropyl, R⁶ is methyl or chloro, each Y¹, Y², Y³, Y⁴and Y⁵ is CR⁴, wherein at least one R⁴ is other than H, fluoro, chloro,methoxy, or difluoro. In another embodiment, one of Y¹, Y², Y³, Y⁴ andY⁵ is N and the rest are independently CR⁴, wherein at least one R⁴ isother than H, or methyl. In another embodiment, two of Y¹, Y², Y³, Y⁴and Y⁵ are N and the rest are independently CR⁴, wherein at least one R⁴is other than H.

In certain embodiments, with respect to the compounds of formula(A-IIIF-2), R⁸ is OH, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴, and thecompound is Compound No. 18 or 20.

In certain embodiments, with respect to the compounds of formula(A-IIIF-2), R⁸ is OH, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴, and thecompound is Compound No. II-20, II-48, II-49, II-52, II-53, II-55,II-156, II-157, or II-158.

In certain embodiments, with respect to the compounds of formula(A-IIIF-2), R⁸ is OH, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴, and thecompound is Compound No. III-6, III-7, III-8, III-64-68, III-74, III-78,III-92, III-95 to III-97, or III-98.

In certain embodiments, with respect to the compounds of formula(A-IIIF-2), each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴, and the compound isCompound No. III-189-191, III-196, III-256 to III-257, or III-258.

In certain embodiments, with respect to the compounds of formula(A-IIIF-2), R⁸ is OH, each Y¹, Y³, Y⁴ and Y⁵ is CR⁴, Y² is N, and thecompound is Compound No. 14, 28, 43, 128, 196, II-87, or III-93.

In certain embodiments, with respect to the compounds of formula (I) or(A-IIIF-2), each Y¹, Y³, Y⁴ and Y⁵ is CR⁴, Y² is N, and the compound isCompound No. II-249, III-192, or III-194.

In certain embodiments, with respect to the compounds of formula (I) or(A-IIIF-2), R⁸ is OH, each Y¹, Y², Y⁴ and Y⁵ is CR⁴, Y³ is N, and thecompound is Compound No. 8, 19, 41, III-69, III-75 to III-82, III-87 toIII-88, III-90, or III-94.

In certain embodiments, with respect to the compounds of formula(A-IIIF-2), each Y¹, Y², Y⁴ and Y⁵ is CR⁴, Y³ is N, and the compound isCompound No. 153, III-187, III-188, III-195 or III-197.

In some embodiments, the compound is of formula (A-IIIF-3), when each R⁷and R⁸ is H; R¹ is methyl; R⁶ is chloro; each Y¹, Y², Y⁴ and Y⁵ is CR⁴,and Y³ is CH, CF or CCl; then at least one of Y¹, Y², Y⁴ and Y⁵ is otherthan CH.

In some embodiments, the compound is of formula (A-IIIF-4), when each R⁷and R⁸ is H, or R⁷ taken together with R⁸ form a —CH₂ moiety, R¹ ismethyl′ R⁶ is F, Cl, CF₃, ethenyl, or propenyl; each Y¹, Y², Y⁴ and Y⁵is CR⁴, and Y³ is CH, CF or CCl; then at least one of Y¹, Y², Y⁴ and Y⁵is other than CH.

In some embodiments, the compound is of formula (A-IIIF-3), when R⁷ is Hor methyl; R⁸ is OH; R⁶ is chloro or iso-propyl; Y² or Y³ is N; then R¹is other than methyl.

In certain embodiments, with respect to the compounds of formula(A-IIIF-3), the compound is Compound No. III-4, III-71, or III-90.

In some embodiments, the compound is of formula (A-IIIF-4), when R⁷ is Hor methyl, R⁸ is OH, R¹ is methyl, R⁶ is Cl, F, or methoxy; then Y³ isother than N.

In certain embodiments, with respect to the compounds of formula(A-IIIF-4), the compound is Compound No. III-5, III-70, III-72, orIII-89.

In another embodiment, the compound is of the formula (A-IIIG-1),(A-IIIG-2) or (A-IIIG-3):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl;

R⁶ is H, hydroxyl, halo, C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, optionally substituted C₁-C₅ alkoxy or optionallysubstituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

each Y¹, Y², Y³, Y⁴ and Y⁵ is independently N or CR⁴ such that no morethan two of Y¹, Y², Y³, Y⁴ and Y⁵ are N, wherein R⁴ is H, halo, CH₃,CF₃, or OCH₃.

In some embodiments, the compound is of the formula (A-IIIG-2). In somevariations, R¹ is H or CH₃. In other variations, R⁷ is H or CH₃. In yetother variations, R⁸ is hydroxyl or NH₂. In yet other variations, eachR⁷ and R⁸ is H. In yet other variations, one of Y¹, Y², Y³, Y⁴ and Y⁵ isN and the other four of Y¹, Y², Y³, Y⁴ and Y⁵ are independently CR⁴, andwherein R⁴ is H, halo, CH₃, CF₃, or OCH₃. In other variations, Y⁵ is CH,and each Y¹, Y², Y³ and Y⁴ is independently N or CR⁴ such that two ofY¹, Y², Y³ and Y⁴ are N, and wherein R⁴ is H, halo, CH₃, CF₃, or OCH₃.In some variations, R⁴ is halo. In other variations, R⁴ is CH₃. In oneembodiment, R⁴ is F. In another embodiment, R⁴ is Cl. In someembodiments, any two of Y¹, Y², Y³, Y⁴ and Y⁵ are CR⁴, and each R⁴ isindependently Cl or F. In one embodiment, each R⁴ is Cl. In anotherembodiment, each R⁴ is F.

In some embodiments, the compound is of the formula (A-IIIG-1),(A-IIIG-2), or (A-IIIG-3), R⁶ is H, R¹ is methyl, each of R⁷ and R⁸ isH, each Y¹, Y², Y³, Y⁴ and Y⁵ is CR⁴ wherein at least one R⁴ is otherthan H.

In certain embodiments, with respect to the compounds of formula(A-IIIG-2), R⁸ is OH, and the compound is Compound No. 55, 136, 138,145, II-99, II-100, II-108, II-109, II-111, or II-114.

In certain embodiments, with respect to the compounds of formula(A-IIIG-2), the compound is Compound No. 156, 159, II-110, II-119,II-240, or V-2.

In another embodiment, the compound is of the formula (A-IIIH):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl;

R⁶ is H, hydroxyl, halo, C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, optionally substituted C₁-C₅ alkoxy or optionallysubstituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

each Y¹, Y², Y³, Y⁴ and Y⁵ is independently N or CR⁴ such that no morethan two of Y¹, Y², Y³, Y⁴ and Y⁵ are N, wherein R⁴ is H, halo, CH₃,CF₃, or OCH₃.

In certain embodiments, with respect to the compounds of formula(A-IIIH), the compound is Compound No. 13, 15, 92, 154, 172, 221, or339.

In certain embodiments, with respect to the compounds of formula(A-IIIH), the compound is Compound No. II-22, II-24 to II-35, II-37,II-38, II-41 to II-46, II-51, II-134, II-135, II-155, II-159, II-246, orII-289.

In certain embodiments, with respect to the compounds of formula(A-IIIH), the compound is Compound No. III-9-46, III-209 to III-220,III-320 to III-351, or III-352.

In certain embodiments, with respect to the compounds of formula(A-IIIH), the compound is Compound No. V-21.

In another embodiment, the compound is of the formula (A-IIIH-1),(A-IIIH-2), (A-IIIH-3) or (A-IIIH-4):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 independentlysubstituents selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl;

R⁶ is H, hydroxyl, halo, C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, optionally substituted C₁-C₅ alkoxy or optionallysubstituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

each Y¹, Y², Y³, Y⁴ and Y⁵ is independently N or CR⁴ such that no morethan two of Y¹, Y², Y³, Y⁴ and Y⁵ are N, wherein R⁴ is H, halo, CH₃,CF₃, or OCH₃.

In some variations, R¹ is H or CH₃. In other variations, R⁷ is H or CH₃.In yet other variations, R⁸ is hydroxyl or NH₂. In yet other variations,each R⁷ and R⁸ is H. In some variations, each Y¹, Y², Y³, Y⁴ and Y⁵ isindependently N or CR⁴ such that no more than two of Y¹, Y², Y³, Y⁴ andY⁵ are N, wherein R⁴ is H, halo, CH₃, CF₃, or OCH₃. one of Y¹, Y², Y³,Y⁴ and Y⁵ is N and the other four of Y¹, Y², Y³, Y⁴ and Y⁵ areindependently CR⁴, and wherein R⁴ is H, halo, CH₃, CF₃, or OCH₃. Inother variations, Y⁵ is CH, and each Y¹, Y², Y³ and Y⁴ is independentlyN or CR⁴ such that two of Y¹, Y², Y³ and Y⁴ are N, and wherein R⁴ is H,halo, CH₃, CF₃, or OCH₃. In some variations, R⁴ is halo. In othervariations, R⁴ is CH₃. In one embodiment, R⁴ is F. In anotherembodiment, R⁴ is Cl. In some embodiments, any two of Y¹, Y², Y³, Y⁴ andY⁵ are CR⁴, and each R⁴ is independently Cl or F. In one embodiment,each R⁴ is Cl. In another embodiment, each R⁴ is F.

In certain embodiments, with respect to the compounds of formula(A-IIIH-2), R⁶ is methyl or chloro, R⁷ is H or methyl, R⁸ is H or OH, Y¹or Y² is independently C—H, C—F, C—Cl, or C-methoxy, and Y³ is otherthan CH, CF, CCl, or C—OCH₃.

In certain embodiments, with respect to the compounds of formula(A-IIIH-2), R⁶ is Cl or methyl, R⁷ is methyl, R⁸ is hydroxyl, and thecompound is Compound No. 221.

In certain embodiments, with respect to the compounds of formula(A-IIIH-2), R⁶ is Cl or methyl, R⁷ is methyl, R⁸ is hydroxyl, and thecompound is Compound No. II-24, II-25, or II-26.

In certain embodiments, with respect to the compounds of formula(A-IIIH-2), R⁶ is Cl or methyl, R⁷ is methyl, R⁸ is hydroxyl, and thecompound is Compound No. III-11 to III-20, III-22, III-26 to III-38, orIII-44 to III-46.

In one aspect, provided is a compound of formula (A-IIIA′):

or a salt, solvate or N-oxide thereof, wherein:

-   -   X, R¹, R^(3a), R⁶, R⁷, R⁸, R⁹, R¹⁰ and Q are as defined for        formula (A-IIIA),    -   R^(4a) is selected from the group consisting of hydrogen; halo;        hydroxyl; cyano; carboxyl; —OC(O)N(R^(14a))R^(15a); and        —C(O)N(R^(14a))R^(15a);    -   R^(4b) is selected from the group consisting of hydrogen, halo,        and optionally substituted C₁-C₅ alkyl;

In one embodiment, when R^(4b) is hydrogen, R^(4a) is other thanhydrogen. In some variations, R^(4a) is halo. In some variations, R^(4a)is chloro. In some variations, R^(4a) is fluoro. In some variations,each R^(4a) and R^(4b) is halo.

In one aspect, provided is a compound of formula (A-IV):

or a salt, solvate or N-oxide thereof, wherein:R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1-3 substituents selected fromhalo, hydroxyl, carboxyl and perhaloalkyl, or —C(O)O—C₁-C₅ alkyl, or istaken together with R^(2a) or R^(3a) to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together withR^(4a) or R^(5a), where present, to form an ethylene (—CH₂CH₂—) moietyor a propylene (—CH₂CH₂CH₂—) moiety;

each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ orR^(5a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R^(3a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety,taken together with R^(4a), where present, to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ orR^(4a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R^(2a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety,taken together with R^(5a), where present, to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety;

R^(4a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R^(3a)to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or is taken together with R¹ to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or is taken together withR^(2a) to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety, or is taken together with R^(5a), where present, to form amethylene (—CH₂—) moiety;

R^(5a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R^(2a)to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or is taken together with R¹ to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or is taken together withR^(3a) to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety, or is taken together with R^(4a), where present, to form amethylene (—CH₂—) moiety;

each R^(2b), R^(3b), R^(4b) and R^(5b) is independently H, optionallysubstituted C₁-C₅ alkyl, optionally substituted alkenyl or optionallysubstituted aryl;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halo, C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, hydroxyl, carboxyl and perhaloalkyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl; and

Q is cycloalkyl, aryl or heteroaryl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In one variation, the compound is of the formula (A-IV), wherein m, nand R¹ are as defined for the formula (A-IV);

R^(2a) is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R¹ or R^(5a), where present, to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together withR^(3a) to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, taken together with R^(4a), where present, to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(3a) is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R¹ or R^(4a), where present, to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together withR^(2a) to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, taken together with R^(5a), where present, to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(4a) is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R^(3a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R¹ to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or istaken together with R^(2a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or is taken together with R^(5a), wherepresent, to form a methylene (—CH₂—) moiety;

R^(5a) is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R^(2a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R¹ to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or istaken together with R^(3a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or is taken together with R^(4a), wherepresent, to form a methylene (—CH₂—) moiety;

each R^(2b), R^(3b), R^(4b) and R^(5b) is independently H or optionallysubstituted C₁-C₅ alkyl;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halogen, C₁-C₅ alkyloptionally substituted with 1 to 3 halogen atoms, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

Q is aryl or heteroaryl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, C₁-C₅ alkyl,C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl, halo-substituted C₃-C₈cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy, cyano, carboxyl, —NHC(O)CH₃and —C(O)NR¹⁶R¹⁷; and

each R¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅alkyl.

In one embodiment, the compound is of formula (A-IV), each of R^(2b),R^(3a), R^(3b), R^(4b), R^(5a) and R^(5b) is H; each R^(2a) and R^(4a)is H, or R^(2a) is taken together with R^(4a), when present, to form anethylene (—CH₂CH₂—) moiety; each R⁶ and R^(6a) is independently CF₃,methyl, Cl, CONHCH₃, COOH, COOCH₃, or F; X is CR⁶; and R¹ is other thanmethyl. In another embodiment, X is CR⁶, R⁶ is F; and R¹ is other thanmethyl.

In one aspect, provided is a compound of formula (A-V):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 halogen atoms orhydroxyl, cycloalkyl optionally substituted with 1 to 3 halogen atoms orhydroxyl, C₂-C₅ alkenyl, or —C(O)OR¹, or is taken together with R^(2a)or R^(3a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R^(4a) or R^(5a),where present, to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety;

each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ orR^(5a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R^(3a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety,taken together with R^(4a), where present, to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ orR^(4a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R^(2a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety,taken together with R^(5a), where present, to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety;

R^(4a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R^(3a)to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or is taken together with R¹ to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or is taken together withR^(2a) to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety, or is taken together with R^(5a), where present, to form amethylene (—CH₂—) moiety;

R^(5a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R^(2a)to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or is taken together with R¹ to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or is taken together withR^(3a) to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety, or is taken together with R^(4a), where present, to form amethylene (—CH₂—) moiety;

each R^(2b), R^(3b), R^(4b) and R^(5b) is independently H, optionallysubstituted C₁-C₅ alkyl, optionally substituted alkenyl or optionallysubstituted aryl;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halo, C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, hydroxyl, carboxyl and perhaloalkyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

s is 0 or 1;

each R⁹ and R¹⁰, where present, is independently H or optionallysubstituted C₁-C₅ alkyl;

R¹⁸ is H or optionally substituted C₁-C₅ alkyl, and

indicates the presence of either an (E) or (Z) double bondconfiguration; and

Q is cycloalkyl, aryl or heteroaryl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In one variation, the compound is of the formula (A-V), wherein m, n andR¹ are as defined for the formula (A-V);

R^(2a) is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R¹ or R^(5a), where present, to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together withR^(3a) to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, taken together with R^(4a), where present, to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(3a) is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R¹ or R^(4a), where present, to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together withR^(2a) to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, taken together with R^(5a), where present, to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(4a) is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R^(3a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R¹ to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or istaken together with R^(2a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or is taken together with R^(5a), wherepresent, to form a methylene (—CH₂—) moiety;

R^(5a) is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R^(2a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R¹ to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or istaken together with R^(3a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or is taken together with R^(4a), wherepresent, to form a methylene (—CH₂—) moiety;

each R^(2b), R^(3b), R^(4b) and R^(5b) is independently H or optionallysubstituted C₁-C₅ alkyl;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halogen, C₁-C₅ alkyloptionally substituted with 1-3 halogen atoms, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

s is 0 or 1;

each R⁹ and R¹⁰, where present, is independently H or optionallysubstituted C₁-C₅ alkyl;

R¹⁸ is H or optionally substituted C₁-C₅ alkyl, and

indicates the presence of either an (E) or (Z) double bondconfiguration;

Q is aryl or heteroaryl optionally substituted with 1-3 substituentsindependently selected from the group consisting of halo, C₁-C₅ alkyl,C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl, halo-substituted C₃-C₈cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy, cyano, carboxyl, NHC(O)CH₃and —C(O)NR¹⁶R¹⁷; and

each R¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅alkyl.

In certain embodiments, with respect to the compounds of formula (A-V),the compound is Compound No. 116, 121, or 132.

In one aspect, provided is a compound of formula (A-VI):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl, or is taken together with R^(2a) or R^(3a) toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or is taken together with R^(4a) or R^(5a), where present, toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;

each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ orR^(5a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R^(3a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety,taken together with R^(4a), where present, to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ orR^(4a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R^(2a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety,taken together with R^(5a), where present, to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety;

R^(4a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R^(3a)to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or is taken together with R¹ to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or is taken together withR^(2a) to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety, or is taken together with R^(5a), where present, to form amethylene (—CH₂—) moiety;

R^(5a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R^(2a)to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or is taken together with R¹ to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or is taken together withR^(3a) to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety, or is taken together with R^(4a), where present, to form amethylene (—CH₂—) moiety;

each R^(2b), R^(3b), R^(4b) and R^(5b) is independently H, optionallysubstituted C₁-C₅ alkyl, optionally substituted alkenyl or optionallysubstituted aryl;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halo, C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, hydroxyl, carboxyl and perhaloalkyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety,or is taken together with R⁹, where present, to form a C₃-C₅ alkylenewhen R⁸ and R¹⁰ are taken together to form a bond;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety, or is taken together with R¹⁰, where present, to form abond;

s is 0 or 1;

each R⁹ and R¹⁰, where present, is independently H or optionallysubstituted C₁-C₅ alkyl;

each R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is independently H or optionallysubstituted C₁-C₅ alkyl; and

Q is acylamino, carbonylalkoxy, acyloxy, aminoacyl, aminocarbonylalkoxyor aminoaryl.

In one variation, the compound is of the formula (A-VI), wherein m, n, Qand R¹ are as defined for the formula (A-VI);

R^(2a) is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R¹ or R^(5a), where present, to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together withR^(3a) to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, taken together with R^(4a), where present, to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(3a) is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R¹ or R^(4a), where present, to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together withR^(2a) to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety, taken together with R^(5a), where present, to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(4a) is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R^(3a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R¹ to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or istaken together with R^(2a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or is taken together with R^(5a), wherepresent, to form a methylene (—CH₂—) moiety;

R^(5a) is H or optionally substituted C₁-C₅ alkyl, or is taken togetherwith R^(2a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R¹ to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or istaken together with R^(3a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or is taken together with R^(4a), wherepresent, to form a methylene (—CH₂—) moiety;

each R^(2b), R^(3b), R^(4b) and R^(5b) is independently H or optionallysubstituted C₁-C₅ alkyl;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halogen, C₁-C₅ alkyloptionally substituted with 1-3 halogen atoms, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H or optionally substituted C₁-C₅ alkyl;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, or —OC(O)C₁-C₅ alkyl optionally substituted with amino;

s is 0 or 1;

each R⁹ and R¹⁰, where present, is independently H or optionallysubstituted C₁-C₅ alkyl; and

each R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is independently H or optionallysubstituted C₁-C₅ alkyl.

In another embodiment, the compound is of formula (A-VIIA), (A-VIIB),(A-VIIC), (A-VIID), (A-VIIE) or (A-VIIF):

or a salt, solvate or N-oxide thereof, wherein:

R¹, where present, is H, C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, C₃-C₈ cycloalkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, C₂-C₅ alkenyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, or —C(O)O—C₁-C₅ alkyl;

each X¹, X², X and U is independently N or CR⁶;

each R⁶ is independently H, hydroxyl, halo, C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents independently selected from halo,hydroxyl, carboxyl and perhaloalkyl, optionally substituted C₁-C₅ alkoxyor optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

each Y¹, Y², Y³, Y⁴ and Y⁵ is independently N or CR⁴ such that no morethan two of Y¹, Y², Y³, Y⁴ and Y⁵ are N, wherein R⁴ is H, halo, CH₃,CF₃, or OCH₃.

In certain embodiments, with respect to the compounds of formula(A-VIIA), R⁸ is OH, and the compound is Compound No. II-107, II-164,II-165, III-2, III-102-107, III-114, III-131, III-135, III-137, orIII-138.

In certain embodiments, with respect to the compounds of formula(A-VIIA), each X¹, X², X and U is independently CR⁶; and the compound isCompound No. 211, III-100, III-200-202, III-207, III-289 to III-296,III-307, III-309, III-316, III-318, or III-319.

In certain embodiments, with respect to the compounds of formula(A-VIIA), each X¹, X², X and U is independently CR⁶, each Y¹, Y³, Y⁴ andY⁵ is independently CR⁴, Y² is N, and the compound is Compound No.III-132, III-133, III-203, III-205, III-294, III-299, III-303, III-306,III-312, or III-315.

In certain embodiments, with respect to the compounds of formula(A-VIIA), each X¹, X², X and U is independently CR⁶, each Y¹, Y², Y⁴ andY⁵ is independently CR⁴, Y³ is N, and the compound is Compound No. 73,154, II-66, III-101, III-108 to III-113, III-115 to III-121, III-125 toIII-130, III-134, III-138, III-198, III-199, III-206 to III-208,III-297, III-298, III-301, III-302, III-305, III-308, III-311, III-314,or III-317.

In certain embodiments, with respect to the compounds of formula(A-VIIA), each X¹, X², and X is CR⁶; U is N, and the compound isCompound No. III-2.

In certain embodiments, with respect to the compounds of formula(A-VIIB), each X¹, X², X and U is independently CR⁶, R⁸ is OH, and thecompound is Compound No. III-59.

In certain embodiments, with respect to the compounds of formula(A-VIIC), each X¹, X², X and U is independently CR⁶, R⁸ is OH, each Y¹,Y², Y⁴ and Y⁵ is independently CR⁴, Y³ is N, and the compound isCompound No. 36, 38, or II-69.

In certain embodiments, with respect to the compounds of formula(A-VIID), each X¹, X², X and U is independently CR⁶, R⁸ is OH, and thecompound is Compound No. III-58.

In certain embodiments, with respect to the compounds of formula(A-VIIE), each X¹, X², X and U is independently CR⁶, R⁸ is OH, and thecompound is Compound No. III-60.

In certain embodiments, with respect to the compounds of formula(A-VIIE), each X¹, X², X and U is independently CR⁶, R⁸ is OH, and thecompound is Compound No. III-56.

In another embodiment, the compound is of formula (A-VIIIA) or(A-VIIIB):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl;

each X¹, X², X and U is independently N or CR⁶;

each R⁶ is independently H, hydroxyl, halo, C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents independently selected from halo,hydroxyl, carboxyl and perhaloalkyl, optionally substituted C₁-C₅ alkoxyor optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety;

each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl, or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene;

R¹³ is H or optionally substituted C₁-C₅ alkyl;

each R¹⁴ and R¹⁵ is independently H or optionally substituted C₁-C₅alkyl; or R¹⁴ and R¹⁵ are taken together to form a C₃-C₅ alkylene; and

Q is aryl or heteroaryl, wherein the aryl or heteroaryl is independentlyoptionally substituted with 1 to 3 substituents including halogen, C₁-C₅alkyl or cycloalkyl, halo-substituted C₁-C₅ alkyl or cycloalkyl, C₁-C₅alkoxy or cycloalkoxy, —CN or —C(O)N(R^(a))R^(b), and wherein each R^(a)and R^(b) is independently H or C₁-C₅ alkyl.

In some variations of the compounds of formula (A-VIIIA) or (A-VIIIB),one of X¹, X², X and U is N, and the other three of X¹, X², X and U isCR⁶. In other variations, two of X¹, X², X and U is N, and the other twoof X¹, X², X and U is CR⁶. In some variations, R⁷ is a C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxyl, —N(R^(7a))(R^(7b)),—C(O)N(R^(7a))(R^(7b)), —C(O)OR^(7a), —C(O)R^(7a). In other variations,R⁷ is an optionally substituted C₃-C₈ cycloalkyl. In some variations,R¹⁰ is an optionally substituted C₃-C₈ cycloalkyl. In other variations,R¹ or R¹² is an optionally substituted C₃-C₈ cycloalkyl. In somevariations, Q is optionally substituted pyridyl, optionally substitutedpyrimidyl, optionally substituted pyrazinyl, or optionally substitutedphenyl.

In some variations of the compounds of formula (A-VIIIA), X¹ is N; eachX² and X is CR⁶, wherein each R⁶ is H; U is CR⁶, wherein each R⁶ is H ormethyl; R¹ is methyl; each R⁷ and R⁸ is H; and Q is other thanunsubstituted pyridyl, or pyridyl substituted with methyl or CF₃.

In some variations of the compounds of formula (A-VIIIA), U is N, eachX¹, X² and X is CR⁶, wherein each R⁶ is H; R¹ is methyl; R⁷ is H ormethyl; R⁸ is H, OH or methyl; and Q is other than unsubstituted phenyl,phenyl substituted with chloro, unsubstituted pyridyl, or pyridylsubstituted with methyl or CF₃.

In some variations of the compounds of formula (A-VIIIA), X² is N, eachX² and X is CR⁶, wherein each R⁶ is H; U is CR⁶, wherein R⁶ is H ormethyl; R¹ is methyl; each of R⁷ and R⁸ is H; and Q is other thanunsubstituted phenyl, unsubstituted pyridyl, or pyridyl substituted withCF₃.

In some variations of the compounds of formula (A-VIIIA), X is N, eachX¹, U and X² is CR⁶, wherein each R⁶ is H; R¹ is methyl; each of R⁷ andR⁸ is H; and Q is other than unsubstituted phenyl.

In some variations of the compounds of formula (A-VIIIA), each X and Uis N, each X¹ and X² is CR⁶, wherein each R⁶ is H; R¹ is methyl; each ofR⁷ and R⁸ is H; and Q is other than unsubstituted phenyl.

In some variations of the compounds of formula (A-VIIIA), the compoundis according to formula (A-VIIIA-1), (A-VIIIA-2), (A-VIIIA-3),(A-VIIIA-4), (A-VIIIA-5), (A-VIIIA-6), or (A-VIIIA-7):

or a salt, solvate or N-oxide thereof, wherein Q, R¹, R⁶, R⁷, and R⁸,are as described for formula (A-VIIIA), and each X¹, U, X², or X (wherepresent) is independently CR⁶.

In one embodiment, the compound is according to formula (A-VIIIA-1),each X¹, U and X² is CR⁶, wherein each R⁶ is H; R¹ is methyl; each of R⁷and R⁸ is H; and Q is other than unsubstituted phenyl.

In one embodiment, the compound is according to formula (A-VIIIA-2),each X¹ and X is CR⁶, wherein each R⁶ is H; U is CR⁶, wherein R⁶ is H ormethyl; R¹ is methyl; each of R⁷ and R⁸ is H; and Q is other thanunsubstituted phenyl, unsubstituted pyridyl, or pyridyl substituted withCF₃.

In one embodiment, the compound is according to formula (A-VIIIA-3),each X¹, X² and X is CR⁶, wherein each R⁶ is H; R¹ is methyl; R⁷ is H ormethyl; R⁸ is H, OH or methyl; and Q is other than unsubstituted phenyl,phenyl substituted with chloro, unsubstituted pyridyl, or pyridylsubstituted with methyl or CF₃.

In one embodiment, the compound is according to formula (A-VIIIA-4),each X² and X is CR⁶, wherein each R⁶ is H; U is CR⁶, wherein R⁶ is H ormethyl; R¹ is methyl; each R⁷ and R⁸ is H; and Q is other thanunsubstituted pyridyl, or pyridyl substituted with methyl or CF₃.

In one embodiment, the compound is according to formula (A-VIIIA-5),each X¹ and X² is CR⁶, wherein each R⁶ is H; R¹ is methyl; each of R⁷and R⁸ is H; and Q is other than unsubstituted phenyl.

In one embodiment, with respect to the compounds of formula (A-VIIIA-1),(A-VIIIA-2), (A-VIIIA-3), (A-VIIIA-4), (A-VIIIA-5), (A-VIIIA-6), or(A-VIIIA-7), each X¹, U, X², or X (where present) is independently CR⁶,and each R⁶ is H. In another embodiment, each R⁶ is independentlyselected from H, C₁-C₅ alkyl, and halo C₁-C₅ alkyl. In certainembodiments, each R⁶ is independently selected from H, methyl, ethyl,fluoro, chloro, CH₂F, and CF₃.

In one embodiment, with respect to the compounds of formula (A-VIIIA-1),(A-VIIIA-2), (A-VIIIA-4), (A-VIIIA-6), or (A-VIIIA-7), each X¹, X², or X(where present) is CH, U is CR⁶, and R⁶ is selected from H, C₁-C₅ alkyl,and halo C₁-C₅ alkyl. In certain embodiments, each R⁶ is independentlyselected from methyl, ethyl, fluoro, chloro, CH₂F, and CF₃.

In one embodiment, with respect to the compounds of formula (A-VIIIA-1),(A-VIIIA-2), (A-VIIIA-3), (A-VIIIA-4), (A-VIIIA-5), (A-VIIIA-6), or(A-VIIIA-7), each R⁷ and R⁸ is H. In another embodiment, R⁷ is H ormethyl, and R⁸ is H, OH or methyl.

In one embodiment, with respect to the compounds of formula (A-VIIIA-1),(A-VIIIA-2), (A-VIIIA-3), (A-VIIIA-4), (A-VIIIA-5), (A-VIIIA-6), or(A-VIIIA-7), Q is optionally substituted phenyl.

In another embodiment, with respect to the compounds of formula(A-VIIIA-1), (A-VIIIA-2), (A-VIIIA-3), (A-VIIIA-4), (A-VIIIA-5),(A-VIIIA-6), or (A-VIIIA-7), Q is phenyl substituted with C₁-C₅ alkyl,halo, halo C₁-C₅ alkyl, or C₁-C₅ alkoxy.

In another embodiment, with respect to the compounds of formula(A-VIIIA-1), (A-VIIIA-2), (A-VIIIA-3), (A-VIIIA-4), (A-VIIIA-5),(A-VIIIA-6), or (A-VIIIA-7), Q is phenyl substituted with methyl, ethyl,fluoro, chloro, methoxy, or CF₃.

In another embodiment, with respect to the compounds of formula(A-VIIIA-1), (A-VIIIA-2), (A-VIIIA-3), (A-VIIIA-4), (A-VIIIA-5),(A-VIIIA-6), or (A-VIIIA-7), Q is optionally substituted pyridyl, oroptionally substituted pyrimidinyl.

In another embodiment, with respect to the compounds of formula(A-VIIIA-1), (A-VIIIA-2), (A-VIIIA-3), (A-VIIIA-4), (A-VIIIA-5),(A-VIIIA-6), or (A-VIIIA-7), Q is pyridyl substituted with C₁-C₅ alkyl,halo, halo or C₁-C₅ alkyl.

In another embodiment, with respect to the compounds of formula(A-VIIIA-1), (A-VIIIA-2), (A-VIIIA-3), (A-VIIIA-4), (A-VIIIA-5),(A-VIIIA-6), or (A-VIIIA-7), Q is pyridyl substituted with methyl,ethyl, fluoro, chloro, or CF₃.

In one embodiment, provided are compounds of formula (A-IXA), (A-IXB),(A-IXC) or (A-IXD):

wherein U, Q, R¹, R⁶, R⁷, and R⁸ are as described for formula (A-I).

In certain embodiments, R⁸ is azido. In certain embodiments, R⁸ isN(R¹¹)R¹². In certain embodiments, each R¹¹ and R¹² is independently Hor optionally substituted C₁-C₅ alkyl, or R¹¹ and R¹² are taken togetherto form C₃-C₅ alkylene. In certain embodiments, R⁷ is H or methyl, R⁸ isazido, or N(R¹¹)R¹², and each R¹¹ and R¹² is independently H oroptionally substituted C₁-C₅ alkyl, or R¹¹ and R¹² are taken together toform C₃-C₅ alkylene. In certain embodiments, R⁸ is SR¹³S(O)R¹³, orSO₂R¹³; and R¹³ is independently H or optionally substituted C₁-C₅alkyl. In one embodiment, R¹³ is methyl, ethyl, i-propyl, n-propyl,n-butyl, or t-butyl. In certain embodiments, R⁷ is C₁-C₅ alkyl,substituted with amino or substituted amino. In certain embodiments, R⁷is C₁-C₅ alkyl, substituted with OH or optionally substituted C₁-C₅alkoxy. In certain embodiments, R⁷ is C₁-C₅ alkyl, substituted with—C(O)N(R^(7a))R^(7b); and each R^(7a) and R^(7b) is independently H oroptionally substituted C₁-C₅ alkyl, or R^(7a) and R^(7b) are takentogether to form C₃-C₅ alkylene. In certain embodiments, R⁷ is C₁-C₅alkyl, substituted with acyl.

In certain embodiments, R⁸ is halo. In one embodiment, with respect tothe compounds of formula (A-IXB) or (A-IXC), when R⁸ is fluoro orchloro, R¹ is methyl, ethyl, i-propyl, or cyclopropyl, R⁷ is H ormethyl, U is CR⁶, and R⁶ is methyl or chloro, then Q is other thanunsubstituted phenyl, phenyl substituted with methoxy, chloro, fluoro,difluoro, unsubstituted pyridyl, pyridyl substituted with methyl, orunsubstituted pyrimidinyl.

In certain embodiments, R⁷ is optionally substituted cycloalkyl. In oneembodiment, with respect to the compounds of formula (A-IXB) or (A-IXC),when R⁷ is optionally substituted cycloalkyl, R⁸ is OH, R¹ is methyl, Uis CR⁶, and R⁶ is methyl or chloro, then Q is other than unsubstitutedphenyl, phenyl substituted with fluoro, or unsubstituted pyridyl. In oneembodiment, R⁷ is optionally substituted cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. In certain embodiments, R⁷ is C₁-C₅ alkyl,substituted with acylamino.

In one embodiment, with respect to the compounds of formula (A-IXB) or(A-IXC), when R⁷ is CH₂—CON(H)CH₃, R¹ is methyl or ethyl, U is CR⁶, andR⁶ is methyl or chloro, then Q is other than phenyl substituted withfluoro, chloro, methoxy, or difluoro, unsubstituted pyridyl, pyridylsubstituted with methyl, or unsubstituted pyrimidinyl.

In certain embodiments, R⁷ is C₁-C₅ alkyl, substituted with—C(O)OR^(7a), and R^(7a) is H or optionally substituted C₁-C₅ alkyl.

In one embodiment, R⁷ is C₁-C₅ alkyl, substituted with —C(O)OR^(7a),R^(7a) is H or optionally substituted C₁-C₅ alkyl, R¹ is methyl orethyl, U is CR⁶, and R⁶ is methyl or chloro; and Q is other than phenylsubstituted with F, chloro, methoxy, or difluoro, unsubstituted pyridyl,pyridyl substituted with methyl, or unsubstituted pyrimidinyl.

In certain embodiments, R⁷ is C₁-C₅ alkyl, substituted with 1-3 halo.

In one embodiment, with respect to the compounds of formula (A-IXB), R⁷is CF₃, R⁸ is OH, R¹ is methyl, U is CR⁶, and R⁶ is methyl; and Q isother than phenyl substituted with fluoro. In one particular embodiment,R⁷ is CF₃.

In certain embodiments, R⁸ is —C(O)N(R¹⁴)R¹⁵; and each R¹⁴ and R¹⁵ isindependently H or optionally substituted C₁-C₅ alkyl, or R¹⁴ and R¹⁵are taken together to form a C₃-C₅ alkylene.

In one particular embodiment, R⁸ is —C(O)N(R¹⁴)R¹⁵; and each R¹⁴ and R¹⁵is independently H or methyl, R¹ is methyl, U is CR⁶, and R⁶ is methyl;and Q is other than cyclobutyl.

In certain embodiments, R⁸ is —OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl,—OC(O)-heteroaryl, —OC(O)C₁-C₅ alkyl optionally substituted with amino,—OC(O)C₁-C₅ alkyl substituted with carboxyl, or —OC₁-C₅ alkyl optionallysubstituted with carboxyl; and each R¹⁴ and R¹⁵ is independently H oroptionally substituted C₁-C₅ alkyl, or R¹⁴ and R¹⁵ are taken together toform a C₃-C₅ alkylene.

In certain embodiments, R⁷ is optionally substituted phenyl. In oneparticular embodiment, R⁷ is optionally substituted phenyl, R⁸ is OH, R¹is methyl or ethyl, U is CR⁶, and R⁶ is methyl or chloro; and Q is otherthan unsubstituted phenyl, phenyl substituted with fluoro orunsubstituted pyridyl.

In certain embodiments, R⁸ is OH. In some embodiments, R⁸ is OH, and R⁷is other than H, or C₁-C₄ alkyl.

In some embodiments, compounds of the formula (B-I) are provided:

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1-3 substituents selected fromhalo, hydroxyl, carboxyl and perhaloalkyl, or —C(O)O—C₁-C₅ alkyl, or istaken together with R^(2a) or R^(3a) to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together withR^(4a) or R^(5a), where present, to form an ethylene (—CH₂CH₂—) moietyor a propylene (—CH₂CH₂CH₂—) moiety;

each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ orR^(5a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R^(3a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety,taken together with R^(4a), where present, to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ orR^(4a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety, or is taken together with R^(2a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety,taken together with R^(5a), where present, to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety;

R^(4a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R^(3a)to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or is taken together with R¹ to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or is taken together withR^(2a) to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety, or is taken together with R^(5a), where present, to form amethylene (—CH₂—) moiety;

R^(5a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R^(2a)to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or is taken together with R¹ to form an ethylene (—CH₂CH₂—)moiety or a propylene (—CH₂CH₂CH₂—) moiety, or is taken together withR^(3a) to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety, or is taken together with R^(4a), where present, to form amethylene (—CH₂—) moiety;

each R^(2b), R^(3b), R^(4b) and R^(5b) is independently H, optionallysubstituted C₁-C₅ alkyl, optionally substituted alkenyl or optionallysubstituted aryl;

X is N or CR^(6a);

t is 1, 2 or 3;

each R⁶ and R^(6a) is independently H, hydroxyl, halo, C₁-C₅ alkyloptionally substituted with 1-3 substituents selected from halo,hydroxyl, carboxyl and perhaloalkyl, optionally substituted C₁-C₅ alkoxyor optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl;

R⁸ is azido, acylamino, carboxyl, carbonylalkoxy, —OC(O)C₁-C₅ alkylsubstituted with carboxyl, or —OC₁-C₅ alkyl optionally substituted withcarboxyl;

each R⁹ and R¹⁰ is independently H or optionally substituted C₁-C₅alkyl; and

Q is cycloalkyl, aryl or heteroaryl optionally substituted with 1-3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In one variation, Q, X, m, n, t, R¹, R^(2a), R^(2b), R^(3a), R^(3b),R^(4a), R^(4b), R^(5a), R^(5b), R⁶, R^(6a), R⁷, R⁹ and R¹⁰ are asdefined for the formula (B-I), and R⁸ is azido, acylamino, —OC(O)C₁-C₅alkyl substituted with carboxyl, or —OC₁-C₅ alkyl substituted withcarboxyl, or a salt, solvate or N-oxide thereof. In another variation,Q, X, m, n, t, R, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b),R^(5a), R^(5b), R⁶, R^(6a), R⁷, R⁹ and R¹⁰ are as defined for theformula (B-I), and R⁸ is carboxyl, or carbonylalkoxy, or a salt, solvateor N-oxide thereof.

In one variation, Q is cycloalkyl, aryl or heteroaryl optionallysubstituted with 1-3 substituents independently selected from the groupconsisting of halo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substitutedC₁-C₅ alkyl, halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈cycloalkoxy, cyano, carboxyl, —NHC(O)CH₃ and —C(O)NR¹¹R¹² where each R¹¹and R¹² is independently H or optionally substituted C₁-C₅ alkyl.

In some variations, R¹ is C₁-C₅ alkyl (e.g., methyl), each R^(2a) andR^(3a) is H, R⁶ is methyl or chloro, and X is CR^(6a) where R^(6a) ismethyl or chloro. In some of these variations, t is 1, 2 or 3. In someof these variations, R⁷ is H or C₁-C₅ alkyl (e.g., methyl). In some ofthese variations, R⁷ is H. In some of these variations, R⁹ is H or C₁-C₅alkyl (e.g., methyl) and R¹⁰ is H. In some of these variations, each R⁹and R¹⁰ is H. In some of these variations, each R⁷, R⁹ and R¹⁰ is H. Insome of these variations, Q is an unsubstituted pyridyl group which maybe attached to the parent structure at any position (e.g., 2-pyridyl,3-pyridyl or 4-pyridyl). In some of these variations, Q is 3-pyridyl or4-pyridyl. In some of these variations, Q is pyridyl substituted amethyl (e.g., 6-methyl-3-pyridyl and 3-methyl-4-pyridyl). In some ofthese variations, Q is phenyl substituted with a halo group (e.g.,fluorophenyl). In some of these variations, Q is 4-fluorophenyl. In someof these variations, Q is phenyl substituted with —C(O)NR¹¹R¹² whereeach R¹¹ and R¹² is H. In some of these variations, Q is4-carbamoylphenyl.

In another embodiment, the compound of formula (B-I) has the formula(B-IA):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1-3 substituents selected fromhalo, hydroxyl, carboxyl and perhaloalkyl, or —C(O)O—C₁-C₅ alkyl, or istaken together with R^(2a) or R^(3a) to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halo, C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, hydroxyl, carboxyl and perhaloalkyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl;

R⁸ is azido, acylamino, carboxyl, carbonylalkoxy, —OC(O)C₁-C₅ alkylsubstituted with carboxyl or —OC₁-C₅ alkyl optionally substituted withcarboxyl;

each R⁹ and R¹⁰ is independently H or optionally substituted C₁-C₅alkyl; and

Q is cycloalkyl, aryl or heteroaryl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In one variation, the compound is of the formula (B-IA), wherein Q, X,R¹, R^(2a), R^(3a), R⁶, R^(6a), R⁷, R⁹ and R¹⁰ are as defined for theformula (B-IA), and R⁸ is azido, acylamino, —OC(O)C₁-C₅ alkylsubstituted with carboxyl, or —OC₁-C₅ alkyl substituted with carboxyl,or a salt, solvate or N-oxide thereof. In another variation, Q, X, R¹,R^(2a), R^(3a), R⁶, R^(6a), R⁷, R⁹ and R¹⁰ are as defined for theformula (B-IA), and R⁸ is carboxyl, or carbonylalkoxy.

In some variations of the compound of the formula (B-IA), each R^(2a)and R^(3a) is H. In some variations, R¹ is C₁-C₅ alkyl (e.g., methyl).In some variations, each R⁶ and R^(6a) is independently halo (e.g.,chloro) or C₁-C₅ alkyl (e.g., methyl). In some variations, each R⁶ andR^(6a) is independently halo (e.g., chloro or fluoro). In somevariations, R⁶ and R^(6a) is chloro. In some variations, each R⁶ andR^(6a) is independently C₁-C₅ alkyl (e.g., methyl). In some variations,X is CR^(6a) where R^(6a) is H or halo. In some variations, X is CR^(6a)where R^(6a) is H. In some variations, X is CR^(6a) where R^(6a) ischloro. In some variations, X is CR^(6a) where R^(6a) is halo (e.g.,chloro or fluoro). In some variations, R⁶ is H or halo. In somevariations, R⁶ is H. In some variations, R⁶ is chloro. In somevariations, R⁶ is halo (e.g., chloro or fluoro). In some variations, R⁷is H or C₁-C₅ alkyl (e.g., methyl). In some variations, X is N. In somevariations, R⁷ is H. In some variations, R⁷ is C₁-C₅ alkyl (e.g.,methyl). In some variations, R⁸ is azido. In some variations, R⁸ iscarboxyl, —OC(O)C₁-C₅ alkyl substituted with carboxyl, or —OC₁-C₅ alkyloptionally substituted with carboxyl. In some variations, R⁸ isacylamino. In some variations, R⁷ is H or C₁-C₅ alkyl (e.g., methyl) andR⁸ is azido, acylamino, —OC(O)C₁-C₅ alkyl substituted with carboxyl or—OC₁-C₅ alkyl optionally substituted with carboxyl. In some variations,R⁷ is H and R⁸ is azido, acylamino, —OC(O)C₁-C₅ alkyl substituted withcarboxyl or —OC₁-C₅ alkyl optionally substituted with carboxyl. In somevariations, R⁹ is H or C₁-C₅ alkyl (e.g., methyl). In some variations,R¹⁰ is H or C₁-C₅ alkyl (e.g., methyl). In some variations, each R⁹ andR¹⁰ is H. In some variations, one of R⁹ and R¹⁰ is H and the other isC₁-C₅ alkyl (e.g., methyl). In some variations, Q is an unsubstitutedheteroaryl (e.g., pyridyl). In some variations, Q is an unsubstitutedpyridyl group which may be attached to the parent structure at anyposition (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl). In some variations,Q is 3-pyridyl or 4-pyridyl. In some variations, Q is heteroarylsubstituted with a substituent selected form the group consisting ofhalo (e.g., fluoro or chloro), C₁-C₅ alkyl (e.g., methyl),halo-substituted C₁-C₅ alkyl (e.g., CF₃) and carboxyl. In somevariations, Q is heteroaryl substituted with halo (e.g., fluoro orchloro) or C₁-C₅ alkyl (e.g., methyl). In some variations, Q isheteroaryl substituted with C₁-C₅ alkyl (e.g., methyl). In somevariations, Q is a pyridyl optionally substituted with a methyl wherethe pyridyl group may be attached to the parent structure at anyposition and the methyl group may be attached to the pyridyl group atany open position (e.g., 6-methyl-3-pyridyl and 3-methyl-4-pyridyl). Insome variations, Q is phenyl substituted with a substituent selectedform the group consisting of halo (e.g., fluoro or chloro), C₁-C₅ alkyl(e.g., methyl), halo-substituted C₁-C₅ alkyl (e.g., CF₃), carboxyl and—C(O)NR¹¹R¹² where each R¹¹ and R¹² is independently H or optionallysubstituted C₁-C₅ alkyl. In some variations, Q is phenyl substitutedwith a halo group (e.g., fluorophenyl). In some variations, Q is4-fluorophenyl. In some variations, Q is phenyl substituted with—C(O)NR¹¹R¹² where each R¹¹ and R¹² is H.

In some variations of the compound of the formula (B-IA), R¹ is C₁-C₅alkyl (e.g., methyl), each R^(2a) and R^(3a) is H, R⁶ is methyl orchloro, and X is CH. In some of these variations, R⁷ is H or C₁-C₅ alkyl(e.g., methyl) and R⁸ is azido. In some of these variations, R⁷ is H andR⁸ is azido, acylamino, —OC(O)C₁-C₅ alkyl substituted with carboxyl or—OC₁-C₅ alkyl optionally substituted with carboxyl. In some of thesevariations, R⁷ is methyl and R⁸ is azido, acylamino, —OC(O)C₁-C₅ alkylsubstituted with carboxyl or —OC₁-C₅ alkyl optionally substituted withcarboxyl. In some of these variations, R⁹ is H or C₁-C₅ alkyl (e.g.,methyl) and R¹⁰ is H. In some of these variations, each R⁹ and R¹⁰ is H.In some of these variations, R⁷ is H or C₁-C₅ alkyl (e.g., methyl), R⁸is azido, and each R⁹ and R¹⁰ is H. In some of these variations, Q is anunsubstituted pyridyl group which may be attached to the parentstructure at any position (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl). Insome of these variations, Q is 3-pyridyl or 4-pyridyl. In some of thesevariations, Q is pyridyl substituted a methyl (e.g., 6-methyl-3-pyridyland 3-methyl-4-pyridyl). In some of these variations, phenyl substitutedwith a halo group (e.g., fluorophenyl). In some of these variations, Qis 4-fluorophenyl. In some of these variations, Q is phenyl substitutedwith —C(O)NR¹¹R¹² where each R¹¹ and R¹² is H. In some of thesevariations, Q is 4-carbamoylphenyl.

In some variations of the compound of the formula (B-IA), R¹ is C₁-C₅alkyl (e.g., methyl), each R^(2a) and R^(3a) is H, R⁶ is methyl orchloro, and X is CH. In some variations, R⁷ is H and R⁸ is azido,acylamino, —OC(O)C₁-C₅ alkyl substituted with carboxyl or —OC₁-C₅ alkyloptionally substituted with carboxyl. In some variations, R⁷ is H and R⁸is azido, acylamino, —OC(O)C₁-C₅ alkyl substituted with carboxyl or—OC₁-C₅ alkyl optionally substituted with carboxyl. In some of thesevariations, R⁹ is H or C₁-C₅ alkyl (e.g., methyl) and R¹⁰ is H. In someof these variations, each R⁹ and R¹⁰ is H. In some of these variations,Q is an unsubstituted pyridyl group which may be attached to the parentstructure at any position (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl). Insome of these variations, Q is 3-pyridyl or 4-pyridyl. In some of thesevariations, Q is pyridyl substituted a methyl (e.g., 6-methyl-3-pyridyland 3-methyl-4-pyridyl). In some of these variations, Q is phenylsubstituted with a halo group (e.g., fluorophenyl). In some of thesevariations, Q is 4-fluorophenyl. In some of these variations, Q isphenyl substituted with —C(O)NR¹¹R¹² where each R¹¹ and R¹² is H. Insome of these variations, Q is 4-carbamoylphenyl.

In some variations of the compound of the formula (B-IA), R¹ and R^(2a)are taken together to form a propylene (—CH₂CH₂CH₂—) moiety and R^(3a)is H. In some of these variations, X is N. In some of these variations,X is CH. In some of these variations, R⁶ is C₁-C₅ alkyl (e.g., methyl)or halo (e.g., chloro). In some of these variations, R⁶ is methyl orchloro. In some of these variations, R⁷ is H or C₁-C₅ alkyl (e.g.,methyl) and R⁸ is azido, acylamino, —OC(O)C₁-C₅ alkyl substituted withcarboxyl or —OC₁-C₅ alkyl optionally substituted with carboxyl. In someof these variations, R⁷ is H and R⁸ is azido, acylamino, —OC(O)C₁-C₅alkyl substituted with carboxyl or —OC₁-C₅ alkyl optionally substitutedwith carboxyl. In some of these variations, R⁷ is methyl and R⁸ isazido, acylamino, —OC(O)C₁-C₅ alkyl substituted with carboxyl or —OC₁-C₅alkyl optionally substituted with carboxyl. In some of these variations,R⁹ is H or C₁-C₅ alkyl (e.g., methyl) and R¹⁰ is H. In some of thesevariations, each R⁹ and R¹⁰ is H. In some of these variations, R⁷ is Hor C₁-C₅ alkyl (e.g., methyl), R⁸ is azido, and each R⁹ and R¹⁰ is H. Insome of these variations, Q is an unsubstituted pyridyl group which maybe attached to the parent structure at any position (e.g., 2-pyridyl,3-pyridyl or 4-pyridyl). In some of these variations, Q is 3-pyridyl or4-pyridyl. In some of these variations, Q is pyridyl substituted amethyl (e.g., 6-methyl-3-pyridyl and 3-methyl-4-pyridyl). In some ofthese variations, Q is phenyl substituted with a halo group (e.g.,fluorophenyl). In some of these variations, Q is 4-fluorophenyl. In someof these variations, Q is phenyl substituted with —C(O)NR¹¹R¹² whereeach R¹¹ and R¹² is H. In some of these variations, Q is4-carbamoylphenyl.

In certain embodiments, with respect to the compounds of formula (B-IA),X is CR⁶, R⁸ is azido, and the compound is Compound No. II-261, II-266,II-276, II-298, V-1, V-3, V-22, or V23.

In certain embodiments, with respect to the compounds of formula (B-IA),X is CR⁶, R⁸ is acylamino, carboxyl, or carbonylalkoxy, and the compoundis Compound No. II-258, II-262, II-263, or II-277.

In certain embodiments, with respect to the compounds of formula (B-IA),X is CR⁶, R⁸ is —OC(O)C₁-C₅ alkyl substituted with carboxyl, and thecompound is Compound No. V-18.

In certain embodiments, with respect to the compounds of formula (B-IA),X is CR⁶, R⁸ is —OC₁-C₅ alkyl optionally substituted with carboxyl, andthe compound is Compound No. II-256, II-274, II-281, V-14 or V-15.

In another embodiment, the compound of formula (B-I) has the formula(B-IB):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1-3 substituents selected fromhalo, hydroxyl, carboxyl and perhaloalkyl, or —C(O)O—C₁-C₅ alkyl, or istaken together with R^(2a) or R^(3a) to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halo, C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, hydroxyl, carboxyl and perhaloalkyl, optionally substitutedC₁-C₅ alkoxy or optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl;

R⁸ is azido, acylamino, carboxyl, carbonylalkoxy, —OC(O)C₁-C₅ alkylsubstituted with carboxyl, or —OC₁-C₅ alkyl optionally substituted withcarboxyl;

each R⁹ and R¹⁰ is independently H or optionally substituted C₁-C₅alkyl; and

Q is cycloalkyl, aryl or heteroaryl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In one variation, the compound is of the formula (B-IB), wherein Q, X,R¹, R^(2a), R^(3a), R⁶, R^(6a), R⁷, R⁹ and R¹⁰ are as defined for theformula (B-IB), and R⁸ is azido, acylamino, —OC(O)C₁-C₅ alkylsubstituted with carboxyl, or —OC₁-C₅ alkyl substituted with carboxyl,or a salt, solvate or N-oxide thereof. In another variation, Q, X, R¹,R^(2a), R^(3a), R⁶, R^(6a), R⁷, R⁹ and R¹⁰ are as defined for theformula (B-IB), and R⁸ is carboxyl, or carbonylalkoxy.

In some variations of the compound of the formula (B-IB), R¹ is C₁-C₅alkyl (e.g., methyl), each R^(2a) and R^(3a) is H, R⁶ is methyl orchloro, and X is CH. In some of these variations, R⁷ is H or C₁-C₅ alkyl(e.g., methyl) and R⁸ is azido. In some of these variations, R⁷ is H andR⁸ is azido, acylamino, —OC(O)C₁-C₅ alkyl substituted with carboxyl or—OC₁-C₅ alkyl optionally substituted with carboxyl. In some of thesevariations, R⁷ is methyl and R⁸ is azido, acylamino, —OC(O)C₁-C₅ alkylsubstituted with carboxyl or —OC₁-C₅ alkyl optionally substituted withcarboxyl. In some of these variations, R⁹ is H or C₁-C₅ alkyl (e.g.,methyl) and R¹⁰ is H. In some of these variations, each R⁹ and R¹⁰ is H.In some of these variations, R⁷ is H or C₁-C₅ alkyl (e.g., methyl), R⁸is azido, acylamino, —OC(O)C₁-C₅ alkyl substituted with carboxyl or—OC₁-C₅ alkyl substituted with carboxyl, and each R⁹ and R¹⁰ is H. Insome of these variations, Q is an unsubstituted pyridyl group which maybe attached to the parent structure at any position (e.g., 2-pyridyl,3-pyridyl or 4-pyridyl). In some of these variations, Q is 3-pyridyl or4-pyridyl. In some of these variations, Q is pyridyl substituted amethyl (e.g., 6-methyl-3-pyridyl and 3-methyl-4-pyridyl). In some ofthese variations, Q is phenyl substituted with a halo group (e.g.,fluorophenyl). In some of these variations, Q is 4-fluorophenyl.

In another embodiment, the compound of formula (B-I) has the formula(B-IC):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1-3 substituents selected fromhalo, hydroxyl, carboxyl and perhaloalkyl, or —C(O)O—C₁-C₅ alkyl, or istaken together with R^(2a) or R^(3a) to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(5a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H, hydroxyl, halo, C₁-C₅ alkyloptionally substituted with 1-3 substituents selected from halo,hydroxyl, carboxyl and perhaloalkyl, optionally substituted C₁-C₅ alkoxyor optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl;

R⁸ is azido, acylamino, carboxyl, carbonylalkoxy, —OC(O)C₁-C₅ alkylsubstituted with carboxyl or —OC₁-C₅ alkyl optionally substituted withcarboxyl;

each R⁹ and R¹⁰ is independently H or optionally substituted C₁-C₅alkyl; and

Q is cycloalkyl, aryl or heteroaryl optionally substituted with 1-3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In one variation, the compound is of the formula (B-IC), wherein Q, X,R¹, R^(2a), R^(3a), R^(5a), R⁶, R^(6a), R⁷, R⁹ and R¹⁰ are as definedfor the formula (B-IC), and R⁸ is azido, acylamino, —OC(O)C₁-C₅ alkylsubstituted with carboxyl, or —OC₁-C₅ alkyl substituted with carboxyl,or a salt, solvate or N-oxide thereof. In another variation, Q, X, R¹,R^(2a), R^(3a), R^(5a), R⁶, R^(6a), R⁷, R⁹ and R¹⁰ are as defined forthe formula (B-IC), and R⁸ is carboxyl, or carbonylalkoxy.

In another embodiment, the compound of formula (B-I) has the formula(B-ID):

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1-3 substituents selected fromhalo, hydroxyl, carboxyl and perhaloalkyl, or —C(O)O—C₁-C₅ alkyl, or istaken together with R^(2a) or R^(3a) to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

R^(2a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R^(3a) is H, optionally substituted C₁-C₅ alkyl, optionally substitutedalkenyl or optionally substituted aryl, or is taken together with R¹ toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H; hydroxyl; halo; C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo, hydroxyl, carboxyl and perhaloalkyl; optionally substitutedC₁-C₅ alkoxy; or optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl;

R⁸ is azido, acylamino, carboxyl, carbonylalkoxy, —OC(O)C₁-C₅ alkylsubstituted with carboxyl, or —OC₁-C₅ alkyl optionally substituted withcarboxyl;

each R⁹ and R¹⁰ is independently H or optionally substituted C₁-C₅alkyl; and

Q is cycloalkyl, aryl or heteroaryl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In one variation, the compound is of the formula (B-ID), wherein Q, X,R¹, R^(2a), R^(3a), R⁶ and R^(6a) are as defined for the formula (B-ID),R⁷ is H, halo, or optionally substituted C₁-C₅ alkyl; R⁸ is azido,acylamino, —OC(O)C₁-C₅ alkyl substituted with carboxyl or —OC₁-C₅ alkylsubstituted with carboxyl; and each R⁹ and R¹⁰ is independently H oroptionally substituted C₁-C₅ alkyl, or a salt, solvate or N-oxidethereof.

In some variations of the compound of the formula (B-ID), R¹ is C₁-C₅alkyl (e.g., methyl), each R^(2a) and R^(3a) is H, R⁶ is methyl orchloro, and X is CH. In some of these variations, R⁷ is H or C₁-C₅ alkyl(e.g., methyl) and R⁸ is azido, acylamino, —OC(O)C₁-C₅ alkyl substitutedwith carboxyl or —OC₁-C₅ alkyl optionally substituted with carboxyl. Insome of these variations, R⁷ is H and R⁸ is azido, acylamino,—OC(O)C₁-C₅ alkyl substituted with carboxyl or —OC₁-C₅ alkyl optionallysubstituted with carboxyl. In some of these variations, R⁷ is methyl andR⁸ is azido, acylamino, —OC(O)C₁-C₅ alkyl substituted with carboxyl or—OC₁-C₅ alkyl optionally substituted with carboxyl. In some of thesevariations, R⁹ is H or C₁-C₅ alkyl (e.g., methyl) and R¹⁰ is H. In someof these variations, each R⁹ and R¹⁰ is H. In some of these variations,R⁷ is H or C₁-C₅ alkyl (e.g., methyl), R⁸ is azido, and each R⁹ and R¹⁰is H. In some of these variations, Q is an unsubstituted pyridyl groupwhich may be attached to the parent structure at any position (e.g.,2-pyridyl, 3-pyridyl or 4-pyridyl). In some of these variations, Q is3-pyridyl or 4-pyridyl. In some of these variations, Q is pyridylsubstituted a methyl (e.g., 6-methyl-3-pyridyl and 3-methyl-4-pyridyl).In some of these variations, Q is phenyl substituted with a halo group(e.g., fluorophenyl). In some of these variations, Q is 4-fluorophenyl.

In one particular embodiment, the compound is of the formula (B-IA),(B-IB), (B-IC) or (B-ID), or a salt, solvate or N-oxide thereof,wherein:

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo and hydroxyl, C₃-C₈ cycloalkyloptionally substituted with 1 to 3 substituents independently selectedfrom halo and hydroxyl, C₂-C₅ alkenyl optionally substituted with 1 to 3substituents independently selected from halo and hydroxyl, or—C(O)O—C₁-C₅ alkyl;

each R^(2a), R^(3a) or R^(5a) (where applicable) is independently H oroptionally substituted C₁-C₅ alkyl;

or R¹ and R^(2a), or R¹ and R^(3a) are taken together to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety;

X is N or CR^(6a);

each R⁶ and R^(6a) is independently H; halogen; C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents selected from halogen atoms andhydroxyl; optionally substituted C₁-C₅ alkoxy; or optionally substituted—C(O)C₁-C₅ alkyl;

each R⁷, R⁹ and R¹⁰ is independently H or optionally substituted C₁-C₅alkyl;

R⁸ is azido, acylamino, —OC(O)C₁-C₅ alkyl substituted with carboxyl or—OC₁-C₅ alkyl optionally substituted with carboxyl; and

Q is aryl or heteroaryl optionally substituted with 1 to 3 substituentsincluding halogen, C₁-C₅ alkyl or cycloalkyl, halo-substituted C₁-C₅alkyl or cycloalkyl, C₁-C₅ alkoxy or cycloalkoxy, —CN, —CO₂H or—C(O)N(R^(a))R^(b) where each R^(a) and R^(b) is independently H orC₁-C₅ alkyl.

In certain embodiments of the compounds of any formula detailed herein,where applicable, such as compounds of the formulae (B-I), (B-IA),(B-IB), (B-IC) and (B-ID), R¹ is H, C₁-C₅ alkyl (e.g., methyl) or—C(O)OR¹¹ where R¹¹ is C₁-C₅ alkyl. It is understood that anydescriptions of R¹ may be combined with any descriptions of othermoieties (e.g., X, R⁶, R^(6a), R⁷, R⁸, R⁹, R¹⁰ and Q) the same as ifeach and every combination were specifically and individually listed.

In certain embodiments of the compounds of any formula detailed herein,where applicable, such as compounds of the formulae (B-I), (B-IA),(B-IB), (B-IC) and (B-ID), each R⁶ and R^(6a) is independently H, CH₃ orCl. It is understood that any descriptions of R⁶ or R^(6a) may becombined with any descriptions of other moieties (e.g., X, R¹, R⁷, R⁸,R⁹, R¹⁰ and Q) the same as if each and every combination werespecifically and individually listed.

In certain embodiments of the compounds of any formula detailed herein,where applicable, such as compounds of the formulae (B-I), (B-IA),(B-IB), (B-IC) and (B-ID), X is N. In certain embodiments of thecompounds of the formulae (B-I), (B-IA), (B-IB), (B-IC) and (B-ID), X isCR^(6a). In some of these embodiments, R^(6a) is H, CH₃ or Cl. It isunderstood that any descriptions of X, R⁶ and R^(6a) may be combinedwith any descriptions of other moieties (e.g., R¹, R⁷, R⁸, R⁹, R¹⁰ andQ) the same as if each and every combination were specifically andindividually listed.

In certain embodiments of the compounds any formula detailed herein,where applicable, such as compounds of the formulae (B-I), (B-IA),(B-IB), (B-IC) and (B-ID), R⁸ is azido. In another variation, R⁸ iscarboxyl. In another variation, R⁸ is carbonylalkoxy. In anothervariation, R⁸ is —OC(O)C₁-C₅ alkyl substituted with carboxyl (e.g.,—OC(O)CH₂CO₂H, —OC(O)CH₂CH₂CO₂H, or —OC(O)CH₂CH₂CH₂CO₂H). In onevariation, R⁸ is —OC₁-C₅ alkyl optionally substituted with carboxyl. Inanother variation, R⁸ is —OC₁-C₅ alkyl substituted with carboxyl (e.g.,—OCH₂CO₂H, —OCH₂CH₂CO₂H, or —OCH₂CH₂CH₂CO₂H). In yet another variation,R⁸ is —OC₁-C₅ alkyl. In another variation, R⁸ is acylamino of theformula —C(O)NR¹³R¹⁴ where each R¹³ and R¹⁴ is independently H oroptionally substituted C₁-C₅ alkyl (e.g., —C(O)NH₂, —C(O)NHCH₃ or—C(O)N(CH₃)₂). In some variations, R⁸ is acylamino of the formula—C(O)NR¹³R¹⁴ where R¹³ and R¹⁴ are joined with the nitrogen to whichthey are attached to form a heterocycle (e.g., —C(O)— pyrrolidinyl). Itis understood that any descriptions of R⁸ may be combined with anydescriptions of other moieties (e.g., X, R¹, R⁶, R^(6a), R⁷, R⁹, R¹⁰ andQ) the same as if each and every combination were specifically andindividually listed.

In certain embodiments of the compounds of any formula detailed herein,where applicable, such as compounds of the formulae (B-I), (B-IA),(B-IB), (B-IC) and (B-ID), Q is aryl or heteroaryl optionallysubstituted with 1, 2 or 3 substituents independently selected form thegroup consisting of halo (e.g., fluoro or chloro), C₁-C₅ alkyl (e.g.,methyl), halo-substituted C₁-C₅ alkyl (e.g., CF₃), carboxyl and—C(O)NR¹¹R¹². In some variations, Q is unsubstituted heteroaryl. In somevariations, Q is aryl or heteroaryl substituted with a substituentselected form the group consisting of halo (e.g., fluoro or chloro),C₁-C₅ alkyl (e.g., methyl), halo-substituted C₁-C₅ alkyl (e.g., CF₃),carboxyl and —C(O)NR¹¹R¹². In some variations, Q is aryl or heteroaryloptionally substituted with 2 substituents independently selected formthe group consisting of halo (e.g., fluoro or chloro), C₁-C₅ alkyl(e.g., methyl), halo-substituted C₁-C₅ alkyl (e.g., CF₃), carboxyl and—C(O)NR¹¹R¹². In some variations, Q is aryl or heteroaryl optionallysubstituted with 3 substituents independently selected form the groupconsisting of halo (e.g., fluoro or chloro), C₁-C₅ alkyl (e.g., methyl),halo-substituted C₁-C₅ alkyl (e.g., CF₃), carboxyl and —C(O)NR¹¹R¹²(e.g., —C(O)NH₂). It is understood that any descriptions of Q may becombined with any descriptions of other moieties (e.g., X, R¹, R⁶,R^(6a), R⁷, R⁸, R⁹ and R¹⁰) the same as if each and every combinationwere specifically and individually listed.

In certain embodiments, with respect to the compounds of formula (B-ID),the compound is Compound No. V-21.

In some embodiments, compounds of the formula (C-I) are provided:

or a salt, solvate or N-oxide thereof, wherein:

R⁶ is H; halo; C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halogen atoms or hydroxyl;C₂-C₅ alkenyl; or —C(O)OR¹¹; or cycloalkyl optionally substituted with 1to 3 halogen atoms or hydroxyl, C₂-C₅ alkenyl, or —C(O)OR¹¹;

R⁷ is H or optionally substituted C₁-C₅ alkyl;

R⁸ is H, hydroxyl, —OC(O)C₁-C₅ alkyl optionally substituted with amino,N(R¹¹)R¹², SR¹³S(O)R¹³ or SO₂R¹³;

each R¹¹, R¹² and R¹³ is independently H or optionally substituted C₁-C₅alkyl;

each X¹, X² and X is N or CH such that no more than two of X¹, X² and Xare N;

each Y¹, Y², Y³ and Y⁴ is N or CR⁴ such that no more than two of Y¹, Y²,Y³ and Y⁴ are N, and wherein R⁴ is H, halo, CH₃, CF₃, or OCH₃; and

n is 0 or 1.

In one variation of formula (C-I), one or more of the following apply(i) n is 1; (ii) R⁶ is other than Cl when n is 0, each R⁷ and R⁸ is H,each X¹, X², X, Y¹, Y² and Y⁴ is CH and Y³ is CF; (iii) R⁶ is other thanH when n is 0 and (iv) R⁶ is other than CH₃ when n is 0, each R⁷ and R⁸is H, each X¹, X², Y¹ and Y⁴ is CH; each X and Y² is N and Y is CCH₃. Inone such variation, R⁶ is a fluoro-containing moiety, such as —CF₃,—CHF₂, —CH₂F, or —CH₂F. In another variation, compounds of the formula(C-I) are provided, wherein the compounds are other than compounds(A)-(G) in Table A.

In one variation, compounds of formula (C-I) are embraced, provided thatat least one of X¹, X² and X is CH. In another variation, at least twoof X¹, X² and X is CH. In one aspect, when at least one or when at leasttwo of X¹, X² and X is CH, one or more of the following apply (i) n is 1and (ii) R⁶ is other than H, C₁ or CH₃. In another variation, when X² isN then X is CH. In another variation, when X² is CH then X is N. In oneaspect, when X² is CH and X is N, then one or more of the followingapply (i) n is 1 and (ii) R⁶ is other than H or CH₃.

In another variation of formula (C-I), R⁶ is halo, CH₃, CH₂F, CHF₂, CF₃or CD₃.

In another variation of formula (C-I), R⁷ is H or CH₃. In one variation,R⁷ is H, CH₃, CF₃, CH₂F, CHF₂ or CH₂OH.

In another variation of formula (C-I), R⁸ is H or OH. In one variation,R⁸ is —OC(O)C₁-C₅ alkyl optionally substituted with amino, N(R¹¹)R¹²,SR¹³, S(O)R¹³ or SO₂R¹³. In one variation, R⁸ is N(R¹¹)R¹². In onevariation, R⁸ is SR¹³, S(O)R¹³ or SO₂R¹³.

In another variation of formula (C-I), at least one of Y¹, Y², Y³ and Y⁴is N. In another variation, Y¹ and Y³ are each N. In another variation,Y² and Y⁴ are each N. In another variation, Y¹ and Y⁴ are each N.

In another variation of formula (C-I), Y¹, Y² and Y⁴ are each H, and Y³is CR⁴, wherein R⁴ is halo, CH₃, CF₃ or OCH₃.

In another variation of formula (C-I), R⁶ is F, Cl, Br, CD₃ or CH₂F; X¹,X² and X are each N or CH; Y² and Y³ are each N or CR⁴, wherein R⁴ isCH₃ or CF₃; R⁴ is H or hydroxyl; and n is 0 or 1. In another variation,of formula (C-I), R⁶ is F, Cl, Br, CD₃ or CH₂F; R⁷ is H, CH₃, CF₃, CH₂F,CHF₂ or CH₂OH; X¹, X² and X are each N or CH; Y² and Y³ are each N orCR⁴, wherein R⁴ is CH₃ or CF₃; R⁸ is H or hydroxyl; and n is 0 or 1. Inone such variation, Y¹ and Y⁴ are both CH.

In certain embodiments, with respect to the compounds of formula (C-I),n is 0, R⁶ is Cl, R⁷ and R⁸ are both H, each X¹, X², X, Y¹, Y² and Y⁴ isCH and Y³ is other than CF.

In one embodiment, the compound is of formula (C-IA) or (C-IB):

wherein R⁶, R⁷, R⁸, X¹, X², X, Y¹, Y², Y³ and Y⁴ are as described forformula (C-I). In one variation of formula (C-IA), one or more of thefollowing apply (i) R⁶ is other than Cl when n is 0, each R⁷ and R⁸ isH, each X¹, X², X, Y¹, Y² and Y⁴ is CH and Y³ is CF; (ii) R⁶ is otherthan H when n is 0 and (iii) R⁶ is other than CH₃ when n is 0, each R⁷and R⁸ is H, each X¹, X², Y¹ and Y⁴ is CH; each X and Y² is N and Y³ isCCH₃. In one such variation, R⁶ is a fluoro-containing moiety, such as—CH₂F. In another variation, compounds of the formula (C-IA) and (C-IB)are provided, wherein the compounds are other than compounds (A)-(G) inTable A.

In certain embodiments, with respect to the compounds of formula (C-IA),X¹ is N, and the compound is Compound No. IV-3, IV-29 to IV-38, IV-109to IV-118, IV-151, IV-152, IV-154 to IV-158, or IV-230 to IV-238.

In certain embodiments, with respect to the compounds of formula (C-IA),X² is N, and the compound is Compound No. II-5 or II-275.

In certain embodiments, with respect to the compounds of formula (C-IB),X is N, and the compound is Compound No. IV-8, IV-49 to IV-58, IV-169 toIV-177, or IV-178.

In certain embodiments, with respect to the compounds of formula (C-IB),X¹ is N, and the compound is Compound No. IV-69 to IV-78, IV-189 toIV-197, or IV-198.

In certain embodiments, with respect to the compounds of formula (C-IB),each of X, X¹, and X² is independently is CR⁶, and the compound isCompound No. 47.

In specific variations, compounds of formula (C-IA) have the structure:

or a salt or solvate thereof, wherein R⁶, X¹, X², X, Y¹, Y², Y³ and Y⁴are defined as for formula (C—I).

In certain embodiments, with respect to the compounds of formula(C-IA-1), each of X, X¹, and X² is independently is CR⁶, and thecompound is Compound No. 197.

In certain embodiments, with respect to the compounds of formula(C-IA-1), each of X, X¹, and X² is independently is CR⁶, and thecompound is No. Compound II-290, IV-6, or IV-7.

In certain embodiments, with respect to the compounds of formula(C-IA-1), X is N, and the compound is Compound No. 74, 134, or 336.

In certain embodiments, with respect to the compounds of formula(C-IA-1), X is N, and the compound is Compound No. II-238, II-243 toII-245, II-268, or II-297.

In certain embodiments, with respect to the compounds of formula(C-IA-1), X is N, and the compound is Compound No. IV-2, IV-4, IV-9,IV-11 to IV-18, IV-89, IV-93 to IV-97, or IV-98.

In certain embodiments, with respect to the compounds of formula(C-IA-1), X¹ is N, and the compound is Compound No. IV-29 to IV-38,IV-109 to IV-117, or IV-118 (Table IV).

In certain embodiments, with respect to the compounds of formula(C-IA-2), the compound is Compound No. II-129, II-168, or II-198.

In certain embodiments, with respect to the compounds of formula(C-IA-2), the compound is Compound No. IV-129 to IV-133, IV-149 toIV-152, IV-154 to IV-158, IV-209, IV-211 to IV-216, IV-219, IV-221,IV-229, IV-230, IV-232, IV-234, IV-236, IV-239, IV-241, IV-242, orIV-244 (Table IV).

In certain embodiments, with respect to the compounds of formula(C-IA-3), each of X, X¹, and X² is independently is CR⁶, and thecompound is Compound No. 176.

In certain embodiments, with respect to the compounds of formula(C-IA-3), each of X, X¹, and X² is independently is CR⁶, and thecompound is Compound No. II-121, II-127, II-128, II-130, II-291, II-294,or IV-7.

In certain embodiments, with respect to the compounds of formula(C-IA-3), X is N, and the compound is Compound No. 26 or 148.

In certain embodiments, with respect to the compounds of formula(C-IA-3), X is N, and the compound is Compound No. II-149.

In certain embodiments, with respect to the compounds of formula(C-IA-3), X is N, and the compound is Compound No. IV-134 to IV-138,IV-210, IV-217, or IV-218.

In certain embodiments, with respect to the compounds of formula(C-IA-3), X¹ is N, and the compound is Compound No. II-17.

In certain embodiments, with respect to the compounds of formula(C-IA-3), X¹ is N, and the compound is Compound No. IV-231, IV-233,IV-235, IV-237, or IV-238.

In other variations, compounds of formula (C-IA) have the structure:

or a salt or solvate thereof, wherein R⁶, R⁷, R⁸, Y¹, Y², Y³ and Y⁴ aredefined as for formula (C-I).

In one variation, R⁷ and R⁸ are both H.

In certain embodiments, with respect to the compounds of formula(C-IA-4), each Y¹, Y², Y³ and Y⁴ is independently CR⁴; and the compoundis Compound No. II-120, II-121, II-266, II-271, or II-279.

In certain embodiments, with respect to the compounds of formula(C-IA-4), each Y¹, Y², Y³ and Y⁴ is independently CR⁴; and the compoundis Compound No. IV-6, IV-7, or IV-9.

In certain embodiments, with respect to the compounds of formula(C-IA-4), one of Y¹, Y², Y³ and Y⁴ is N, and the rest of Y¹, Y², Y³ andY⁴ are independently CR⁴; and the compound is Compound No. 129, 168,197, or 198.

In certain embodiments, with respect to the compounds of formula(C-IA-4), one of Y¹, Y², Y³ and Y⁴ is N, and the rest of Y¹, Y², Y³ andY⁴ are independently CR⁴; and the compound is Compound No. II-125,II-127, II-128, II-130, II-131, II-281, II-282, II-284, II-290, II-291,or II-293.

In certain embodiments, with respect to the compounds of formula(C-IA-4), one of Y¹, Y², Y³ and Y⁴ is N, and the rest of Y¹, Y², Y³ andY⁴ are independently CR⁴; and the compound is Compound No. IV-4, IV-5,IV-15, or IV-18.

In certain embodiments, with respect to the compounds of formula(C-IA-4), two of Y¹, Y², Y³ and Y⁴ are N, and the rest of Y¹, Y², Y³ andY⁴ are independently CR⁴; and the compound is Compound No. 176.

In certain embodiments, with respect to the compounds of formula(C-IA-4), two of Y¹, Y², Y³ and Y⁴ are N, and the rest of Y¹, Y², Y³ andY⁴ are independently CR⁴; and the compound is Compound No. II-6, II-7,II-261, II-276, or II-294.

In certain embodiments, with respect to the compounds of formula(C-IA-5), each Y¹, Y², Y³ and Y⁴ is independently CR⁴; and the compoundis Compound No. 336.

In certain embodiments, with respect to the compounds of formula(C-IA-5), each Y¹, Y², Y³ and Y⁴ is independently CR⁴; and the compoundis Compound No. II-149. In certain embodiments, with respect to thecompounds of formula (C-IA-5), each Y¹, Y², Y³ and Y⁴ is independentlyCR⁴; and the compound is Compound No. II-149a, II-149b, II-149c, orII-149d.

In certain embodiments, with respect to the compounds of formula(C-IA-5), each Y¹, Y², Y³ and Y⁴ is independently CR⁴; and the compoundis Compound No. IV-1, IV-9, IV-11 to IV-18, IV-129, IV-130 to IV-137, orIV-138.

In certain embodiments, with respect to the compounds of formula(C-IA-5), one or two of Y¹, Y², Y³ and Y⁴ is N, and the rest of Y¹, Y²,Y³ and Y⁴ are independently CR⁴; and the compound is Compound No. 26,74, 134, 137, or 148.

In certain embodiments, with respect to the compounds of formula(C-IA-5), one or two of Y¹, Y², Y³ and Y⁴ is N, and the rest of Y¹, Y²,Y³ and Y⁴ are independently CR⁴; and the compound is Compound No. II-79,II-238, II-243, II-244, II-245, II-268, or II-297.

In certain embodiments, with respect to the compounds of formula(C-IA-5), one or two of Y¹, Y², Y³ and Y⁴ is N, and the rest of Y¹, Y²,Y³ and Y⁴ are independently CR⁴; and the compound is Compound No. IV-2,IV-4, IV-89, IV-91, IV-93 to IV-98, IV-209, IV-210, IV-211, IV-213 toIV-217, or IV-218.

In other variations, compounds of formula (C-IA) have the structure:

or a salt or solvate thereof, wherein X is C or N; and R⁶, Y¹, Y², Y³and Y⁴ are defined as for formula (C-I).

In certain embodiments, with respect to the compounds of formula(C-IA-6), the compound is Compound No. 129, 168, or 198.

In certain embodiments, with respect to the compounds of formula(C-IA-6), the compound is Compound No. II-79, II-120, II-125, II-131, orII-293.

In certain embodiments, with respect to the compounds of formula(C-IA-6), the compound is Compound No. IV-129 to IV-133, IV-209, IV-211,IV-213 to IV-215, or IV-216.

In other variations, compounds of formula (C-IA) have the structure:

or a salt or solvate thereof, wherein R⁶, Y¹, Y², Y³ and Y⁴ are definedas for formula (C-I).

In certain embodiments, with respect to the compounds of formula(C-IA-7); the compound is Compound No. 74, 134, 137, or 336.

In certain embodiments, with respect to the compounds of formula(C-IA-7); the compound is Compound No. II-238, II-243, II-244, II-245,or II-297.

In certain embodiments, with respect to the compounds of formula(C-IA-7); the compound is Compound No. IV-2, IV-4, IV-9, IV-11, IV-13 toIV18, IV-89, IV-91, IV-93 to IV-97, or IV-98.

In one variation of formula (C-IA-1) one or more of the following apply:(i) R⁶ is other than Cl when each X¹, X², X, Y¹, Y² and Y⁴ is CH and Y³is CF; (ii) R⁶ is other than H when each X¹, X², X, Y¹, Y² and Y⁴ is CHand Y³ is CF; (iii) R⁶ is other than H when each X¹, X², Y¹ and Y⁴ isCH; each X and Y² is N and Y³ is CCH₃; and (iv) R⁶ is other than CH₃when each X¹, X², Y¹ and Y⁴ is CH; each X and Y² is N and Y³ is CCH₃.

In one variation of formula (C-IA-2), R⁶ is other than H when each X¹,X², Y¹, Y² and Y⁴ is CH; each X and Y³ is N.

In one variation of formula (C-IA-3), R⁶ is other than H when each X¹,X², X, Y¹, Y² and Y⁴ is CH and Y³ is N.

In certain embodiments, with respect to the compounds of formula (C-IA),(C-IA-1), (C-IA-3), or (C-IA-7), n is 0, R⁶ is Cl, R⁷ and R⁸ are both H,each X¹, X², X, Y¹, Y² and Y⁴ is CH and Y³ is other than CF.

In specific variations, compounds of formula (C-IB) have the structure:

or a salt or solvate thereof, wherein R⁶, X¹, X², X, Y¹, Y², Y³ and Y⁴are defined as for formula (C-I).

In certain embodiments, with respect to the compounds of formula(C-IB-1); the compound is Compound No. IV-8, IV-49 to IV-87, or IV-88.

In certain embodiments, with respect to the compounds of formula(C-IB-2); the compound is Compound No. 47.

In certain embodiments, with respect to the compounds of formula(C-IB-2); the compound is Compound No. IV-179 to IV-188, IV-199 toIV-207, or IV-208.

In certain embodiments, with respect to the compounds of formula(C-IB-3); the compound is Compound No. IV-169 to IV-178, IV-190 toIV-197, or IV-198.

In one embodiment, the compound is of formula (C-IC-1):

or a salt or solvate thereof, wherein R⁶, X¹, X², X, Y¹, Y², Y³ and Y⁴are defined as for formula (C-I).

In one embodiment, the compound is of formula (C-II):

wherein R⁶, R⁷, R⁸, X¹, X², X, Y² and Y³ are as described for formula(C-I). In one variation of formula (C-II), one or more of the followingapply (i) n is 1 and (ii) R⁶ is other than Cl when n is 0, each R⁷ andR⁸ is H, each X¹, X², X, Y¹, Y² and Y⁴ is CH and Y³ is CF; (iii) R⁶ isother than H when n is 0 and (iv) R⁶ is other than CH₃ when n is 0, eachR⁷ and R⁸ is H, each X¹, X², Y¹ and Y⁴ is CH; each X and Y² is N and Yis CCH₃. In one such variation, R⁶ is a fluoro-containing moiety, suchas —CH₂F. In another variation, compounds of the formula (C-II) areprovided, wherein the compounds are other than compounds (A)-(G) inTable A.

In one embodiment, the compound is of formula (C-IIA) or (C-IIB):

wherein R⁶, R⁷, R⁸, R¹, X¹, X², X, Y², and Y³ are as described forformula (C-I). In one variation of formula (C-IIA), one or more of thefollowing apply (i) R⁶ is other than Cl when n is 0, each R⁷ and R⁸ isH, each X¹, X², X, Y² is CH and Y³ is CF; (ii) R⁶ is other than H when nis 0 and (iii) R⁶ is other than CH₃ when n is 0, each R⁷ and R⁸ is H,each X¹ and X² is CH; each X and Y² is N and Y³ is CCH₃. In onevariation, the compound of formula (C-IIA) is selected from Compounds(A)-(G), presented in Table A. In another variation, the compound offormula (C-IIA) is other than Compounds (A)-(G) in Table A. It isunderstood that each of compounds (A)-(G) may exist as individualisomers, e.g., isomer A1 and isomer A2 for compound A.

TABLE A Representative Compounds of formula (C-IIA) Compound R⁶ R⁷ R⁸ X¹X² X Y² Y³ A Cl H H CH CH CH CH CF B H H H CH CH CH CH CH C H CH₃ OH CHCH CH CH N D CH₃ H H CH CH N N CCH₃ E H H H CH CH N N CCH₃ F H H H CH CHN N CCF₃ G H H OH CH CH N CH N

In one embodiment, the compound is of formulae (C-IIIA)-(C-IIIF):

wherein R⁶, R⁷, R⁸, X¹, X², X, Y², Y³ and n are as described for formula(C-I). In one variation, the compound is of formula (C-IIIA), (C-IIIB),(C-IIIC), (C-IIID), (CIII-E) or (C-IIIF), wherein n is 0. In onevariation compound is of formulae (C-IIIA), (C-IIIB), (C-IIIC),(C-IIID), (CIII-E) or (C-IIIF), wherein n is 0, and where in one or moreof the following provisions apply: (i) R⁶ is other than Cl when n is 0,each R⁷ and R⁸ is H, each X¹, X², X, Y¹, Y² and Y⁴ is CH. and Y³ is CF;(ii) R⁶ is other than H when n is 0 and (iii) R⁶ is other than CH₃ whenn is 0, each R⁷ and R⁸ is H, each X¹, X², Y¹ and Y⁴ is CH; each X and Y²is N and Y³ is CCH₃. In another variation, the compound is of formulae(C-IIIA), (C-IIIB), (C-IIIC), (C-IIID), (CIII-E) or (C-IIIF), wherein nis 1.

In another embodiment the compound is according to formula (C-IVA),(C-IVB), (C-IVC), (C-IVD), (C-IVE), (C-IVF) or (C-IVG):

or a salt, solvate or N-oxide thereof, wherein:

n is 0 or 1;

each X¹, U, X², or X, where present, is independently CR⁶;

R⁶ is H, hydroxyl, halo, C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, optionally substituted C₁-C₅ alkoxy or optionallysubstituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety; and

Q is cycloalkyl, aryl or heteroaryl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.

In one embodiment, with respect to the compounds of formula (C-IVA),(C-IVB), (C-IVC), (C-IVD), (C-IVE), (C-IVF), or (C-IVG), each X¹, U, X²,or X is independently CR⁶, and each R⁶ is H. In another embodiment, eachR⁶ is independently selected from H, C₁-C₅ alkyl, and halo C₁-C₅ alkyl.In certain embodiments, each R⁶ is independently selected from H,methyl, ethyl, fluoro, chloro, CH₂F, and CF₃.

In one embodiment, with respect to the compounds of formula (C-IVA),(C-IVB), (C-IVD), (C-IVF) or (C-IVG), each X¹, X² and X (where present)is CR⁶, wherein R⁶ is H; U is CR⁶, wherein R⁶ is selected from H, C₁-C₅alkyl and halo C₁-C₅ alkyl. In certain embodiments, each R⁶ isindependently selected from methyl, ethyl, fluoro, chloro, CH₂F, andCF₃.

In one embodiment, with respect to the compounds of formula (C-IVA),(C-IVB), (C-IVC), (C-IVD), (C-IVE), (C-IVF) or (C-IVG), each R⁷ and R⁸is H. In another embodiment, R⁷ is H or methyl, and R⁸ is H, OH ormethyl.

In certain embodiments, with respect to the compounds of formula(C-IVA), (C-IVB), (C-IVC), (C-IVD), (C-IVE), (C-IVF) or (C-IVG), R⁷ isH; and R⁸ is OH, NH₂, CF₃ or methyl.

In one embodiment, with respect to the compounds of formula (C-IVA),(C-IVB), (C-IVC), (C-IVD), (C-IVE), (C-IVF) or (C-IVG), Q is optionallysubstituted phenyl.

In another embodiment, with respect to the compounds of formula (C-IVA),(C-IVB), (C-IVC), (C-IVD), (C-IVE), (C-IVF) or (C-IVG), Q is phenylsubstituted with C₁-C₅ alkyl, halo, halo C₁-C₅ alkyl or C₁-C₅ alkoxy.

In another embodiment, with respect to the compounds of formula (C-IVA),(C-IVB), (C-IVC), (C-IVD), (C-IVE), (C-IVF), or (C-IVG), Q is phenylsubstituted with methyl, ethyl, fluoro, chloro, methoxy or CF₃. Incertain embodiments, Q is phenyl substituted with 4-methyl, 4-ethyl,4-fluoro, 4-chloro, 4-methoxy, or 4-CF₃.

In another embodiment, with respect to the compounds of formula (C-IVA),(C-IVB), (C-IVC), (C-IVD), (C-IVE), (C-IVF), or (C-IVG), Q is optionallysubstituted pyridyl, or optionally substituted pyrimidinyl.

In another embodiment, with respect to the compounds of formula (C-IVA),(C-IVB), (C-IVC), (C-IVD), (C-IVE), (C-IVF), or (C-IVG), Q is pyridylsubstituted with C₁-C₅ alkyl, halo, halo or C₁-C₅ alkyl.

In another embodiment, with respect to the compounds of formula (C-IVA),(C-IVB), (C-IVC), (C-IVD), (C-IVE), (C-IVF), or (C-IVG), Q is pyridylsubstituted with methyl, ethyl, fluoro, chloro, or CF₃.

In one embodiment, with respect to the compounds of formula (C-IVA),(C-IVB), (C-IVC), (C-IVD), (C-IVE), (C-IVF), or (C-IVG), n is 0. Inanother embodiment, n is 1.

In certain embodiments, with respect to the compounds of formula(C-IVA), (C-IVB), (C-IVC), (C-IVD), (C-IVE), (C-IVF) or (C-IVG), thecompound is any one of compounds listed in Table IV. In anotherembodiment, with respect to the compounds of formula (C-IVA), (C-IVB),(C-IVC), (C-IVD), (C-IVE), (C-IVF), or (C-IVG), the compound is any oneof compounds listed in Table IV, provided that the compound is otherthan Compound No. IV-2, IV-4, IV-5, IV-6, or IV-7.

In certain embodiments, with respect to the compounds of formula(C-IVA), n is 0, Q is optionally substituted 4-pyridyl, and the compoundis Compound No. II-79, II-89, II-209, or II-244.

In certain embodiments, with respect to the compounds of formula(C-IVA), n is 0, Q is optionally substituted 3-pyridyl, and the compoundis Compound No. 26, 74, 134, 137, 148, II-238, II-243, II-268, II-297,IV-2, IV-4, IV-97 to IV-98, IV-210, IV-217, or IV-218.

In certain embodiments, with respect to the compounds of formula(C-IVA), n is 0, Q is optionally substituted 2-pyridyl, and the compoundis Compound No. IV-91, IV-95, IV-96, IV-211, IV-215, or IV-216.

In certain embodiments, with respect to the compounds of formula(C-IVA), n is 0, Q is optionally substituted pyrimidyl, and the compoundis Compound No. IV-93 or IV-213.

In certain embodiments, with respect to the compounds of formula(C-IVA), n is 0, Q is optionally substituted pyrazinyl, and the compoundis Compound No. II-245, IV-94, or IV-214.

In certain embodiments, with respect to the compounds of formula(C-IVA), n is 0, Q is optionally substituted phenyl, and the compound isCompound No. 336, II-149, IV-1, IV-9, IV-11 to IV-18, IV-129 to IV-137,or IV-138.

In certain embodiments, with respect to the compounds of formula(C-IVA), n is 1, Q is optionally substituted phenyl, and the compound isCompound No. IV-49 to IV-58, or IV-178.

In certain embodiments, with respect to the compounds of formula(C-IVA), n is 1, Q is optionally substituted 3-pyridyl, and the compoundis Compound No. IV-8.

In certain embodiments, with respect to the compounds of formula(C-IVB), n is 0, and the compound is Compound No. II-5 or II-275.

In certain embodiments, with respect to the compounds of formula(C-IVD), n is 0, and the compound is Compound IV-3, IV-29 to IV-38,IV-109 to IV-118, IV-149 to IV-158, IV-229 to IV-237, or IV-238.

In certain embodiments, with respect to the compounds of formula(C-IVD), n is 1, and the compound is Compound No. IV-69 to IV-78, IV-189to IV-197, or IV-198.

In certain embodiments, with respect to the compounds of formula(C-IVF), the compound is Compound No. IV-19 to IV-21, IV-25 to IV-28,IV-59 to IV-68, IV-100 to IV-108, IV-139 to IV-148, IV-179 to IV-188,IV-219 to IV-227 or IV-228.

In certain embodiments, with respect to the compounds of formula(C-IVG), the compound is Compound No. IV-10, IV-39 to IV-48, IV-79 toIV-88, IV-90, IV-92, IV-119 to IV-128, IV-159 to IV-168, IV-199 toVI-208, IV-212, IV-239 to IV-243, or IV-244.

In one embodiment, compounds of formula (C-VA) or (C-VB) are provided:

or a salt, solvate or N-oxide thereof, wherein:

each X¹, X², X and U is independently N or CR⁶;

each R⁶ is independently H, hydroxyl, halo, C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents independently selected from halo,hydroxyl, carboxyl and perhaloalkyl, optionally substituted C₁-C₅ alkoxyor optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety;

Q is aryl or heteroaryl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, C₁-C₅ alkyl,C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl, halo-substituted C₃-C₈cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy, cyano, carboxyl, —NHC(O)CH₃and —C(O)NR¹⁶R¹⁷; and

each R¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅alkyl.

In some embodiments, compounds of the formula (D-I) are provided:

or a salt, solvate or N-oxide thereof, wherein:

R⁶ is H, halo, C₁-C₅ alkyl or cycloalkyl optionally substituted with 1to 3 halogen atoms or hydroxyl, C₂-C₅ alkenyl, or —C(O)OR¹¹;

R⁷ is H or optionally substituted C₁-C₅ alkyl;

R⁸ is H, hydroxyl, —OC(O)C₁-C₅ alkyl optionally substituted with amino,N(R¹¹)R¹², SR¹³S(O)R¹³ or SO₂R¹³;

each R¹¹, R¹² and R¹³ is independently H or optionally substituted C₁-C₅alkyl;

each X¹, X² and X is N or CH such that no more than two of X¹, X² and Xare N;

each Y¹, Y², Y³ and Y⁴ is N or CR⁴ such that no more than two of Y¹, Y²,Y³ and Y⁴ are N, and wherein R⁴ is H, halo, CH₃, CF₃, or OCH₃; and

n is 0 or 1.

In one variation, the compound is of formula (D-IIA) or (D-IIB):

or a salt or solvate thereof, wherein R⁶, X¹, X², X, Y² and Y³ aredefined as for formula (D-I).

In other variations, compounds of formula (D-IIA) have the structure:

or a salt or solvate thereof, wherein R⁶, R⁷, R⁸, Y¹, Y¹, Y² and Y⁴ aredefined as for formula (D-I).

In certain embodiments, with respect to the compounds of formula(D-IIB), the compound is Compound No. 75.

In certain embodiments, with respect to the compounds of formula(D-IIA-1), the compound is Compound No. 76, III-122, III-356, III-358,or III-359.

In certain embodiments, with respect to the compounds of formula(D-IIA-2), the compound is Compound No. 37, II-86, II-234, II-235,II-236, or II-239.

In one embodiment, compounds of formula (D-IIIA) or (D-IIIB) areprovided:

or a salt, solvate or N-oxide thereof, wherein:

each X¹, X², X and U is independently N or CR⁶;

each R⁶ is independently H, hydroxyl, halo, C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents independently selected from halo,hydroxyl, carboxyl and perhaloalkyl, optionally substituted C₁-C₅ alkoxyor optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl, or is taken together with R⁸ and the carbon atom towhich they are attached to form a dioxolane ring or a carbonyl moiety;

R⁸ is H, halo, hydroxyl, N(R¹¹)R¹², SR¹³, S(O)R¹³, SO₂R¹³,—OC(O)N(R¹⁴)R¹⁵, —OC(O)-aryl, —OC(O)-heteroaryl, or —OC(O)C₁-C₅ alkyloptionally substituted with amino, or is taken together with R⁷ and thecarbon atom to which they are attached to form a dioxolane ring or acarbonyl moiety;

Q is aryl or heteroaryl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, C₁-C₅ alkyl,C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl, halo-substituted C₃-C₈cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy, cyano, carboxyl, —NHC(O)CH₃and —C(O)NR¹⁶R¹⁷; and

each R¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅alkyl.

In certain embodiments, with respect to the compounds of formula(D-IIIA), each X¹, U, X², and X is independently CR⁶, and the compoundis Compound 75, or 76 (Table I); or III-122, III-125, III-126, III-131,III-134, III-135, III-203, III-207, III-208, III-301, III-305, III-314,III-356, III-358, or III-359.

In certain embodiments, with respect to the compounds of formula(D-IIIA), each X¹, U, and X² is independently CR⁶, X is N, and thecompound is Compound No. 37, II-86, II-234, II-235, II-236, or II-239.

In certain embodiments, with respect to the compounds of formula(D-IIIB), the compound is Compound No. III-54, III-353, or III-354.

In some embodiments, compounds of the formula (E-I) are provided:

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl or cycloalkyl optionally substituted with 1 to 3halogen atoms or hydroxyl, C₂-C₅ alkenyl, or —C(O)OR¹¹;

R⁶ is H, halo, C₁-C₅ alkyl or cycloalkyl optionally substituted with 1to 3 halogen atoms or hydroxyl, C₂-C₅ alkenyl, or —C(O)OR¹¹;

R⁷ is H or optionally substituted C₁-C₅ alkyl;

R⁸ is H, hydroxyl, —OC(O)C₁-C₅ alkyl optionally substituted with amino,N(R¹¹)R¹², SR¹³S(O)R¹³ or SO₂R¹³;

each R¹¹, R¹² and R¹³ is independently H or optionally substituted C₁-C₅alkyl;

each X¹, X² and X is N or CH such that no more than two of X¹, X² and Xare N;

each Y¹, Y², Y³ and Y⁴ is N or CR⁴ such that no more than two of Y¹, Y²,Y³ and Y⁴ are N, and wherein R⁴ is H, halo, CH₃, CF₃, or OCH₃; and

n is 0 or 1.

In one variation, the compound is of formula (E-IIA) or (E-IIB):

or a salt or solvate thereof, wherein R¹, R⁶, X¹, X², X, Y² and Y³ aredefined as for formula (E-I).

In other variations, compounds of formula (E-IIA) have the structure:

or a salt or solvate thereof, wherein R¹, R⁶, R⁷, R⁸, Y¹, Y², Y³ and Y⁴are defined as for formula (E-I).

In certain embodiments, with respect to the compounds of formula(E-IIA), the compound is Compound No. III-61.

In some embodiments, compounds of the formula (F-I) are provided:

or a salt, solvate or N-oxide thereof, wherein:

R⁶ is H, halo, C₁-C₅ alkyl or cycloalkyl optionally substituted with 1to 3 halogen atoms or hydroxyl, C₂-C₅ alkenyl, or —C(O)OR¹¹;

R⁷ is H or optionally substituted C₁-C₅ alkyl;

R⁸ is H, hydroxyl, —OC(O)C₁-C₅ alkyl optionally substituted with amino,N(R¹¹)R¹², SR¹³S(O)R¹³ or SO₂R¹³;

each R¹¹, R¹² and R¹³ is independently H or optionally substituted C₁-C₅alkyl;

each X¹, X² and X is N or CH such that no more than two of X¹, X² and Xare N;

each Y¹, Y², Y³ and Y⁴ is N or CR⁴ such that no more than two of Y¹, Y²,Y³ and Y⁴ are N, and wherein R⁴ is H, halo, CH₃, CF₃, or OCH₃; and

n is 0 or 1.

In one variation, the compound is of formula (F-IIA) or (F-IIB):

or a salt or solvate thereof, wherein R⁶, X¹, X², X, Y² and Y³ aredefined as for formula (F-I).

In other variations, compounds of formula (F-IIA) have the structure:

or a salt or solvate thereof, wherein R⁶, R⁷, R⁸, Y¹, Y², Y³ and Y⁴ aredefined as for formula (F-I).

In certain embodiments, with respect to the compounds of formula(F-IIA), the compound is Compound No. III-54, III-353, or III-354.

In some embodiments, compounds of the formula (G-I) are provided:

or a salt, solvate or N-oxide thereof, wherein:

R¹ is H, C₁-C₅ alkyl or cycloalkyl optionally substituted with 1 to 3halogen atoms or hydroxyl, C₂-C₅ alkenyl, or —C(O)OR¹¹;

R⁶ is H, halo, C₁-C₅ alkyl or cycloalkyl optionally substituted with 1to 3 halogen atoms or hydroxyl, C₂-C₅ alkenyl, or —C(O)OR¹¹;

R⁷ is H or optionally substituted C₁-C₅ alkyl;

R⁸ is H, hydroxyl, —OC(O)C₁-C₅ alkyl optionally substituted with amino,N(R¹¹)R¹², SR¹³S(O)R¹³ or SO₂R¹³;

each R¹¹, R¹² and R¹³ is independently H or optionally substituted C₁-C₅alkyl;

each X¹, X² and X is N or CH such that no more than two of X¹, X² and Xare N;

each Y¹, Y², Y³ and Y⁴ is N or CR⁴ such that no more than two of Y¹, Y²,Y³ and Y⁴ are N, and wherein R⁴ is H, halo, CH₃, CF₃, or OCH₃; and

n is 0 or 1.

In one variation, the compound is of formula (G-IIA) or (G-IIB):

or a salt or solvate thereof, wherein R¹, R⁶, X¹, X², X, Y² and Y³ aredefined as for formula (G-I).

In other variations, compounds of formula (G-IIA) have the structure:

or a salt or solvate thereof, wherein R⁶, R⁷, R⁸, Y¹, Y², Y³ and Y⁴ aredefined as for formula (G-I).

In certain embodiments, with respect to the compounds of formula (G-I),n is 0, R⁸ is OH, and the compound is Compound No. III-57.

In one embodiment, compounds of formula (H-IA), (H-IB), (H-IC) or (H-ID)are provided:

or a salt, solvate or N-oxide thereof, wherein:

each X¹, X², X and U is independently N or CR⁶;

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl;

each R⁶ is independently H, hydroxyl, halo, C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents independently selected from halo,hydroxyl, carboxyl and perhaloalkyl, optionally substituted C₁-C₅ alkoxyor optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl;

Q is aryl or heteroaryl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, C₁-C₅ alkyl,C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl, halo-substituted C₃-C₈cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy, cyano, carboxyl, —NHC(O)CH₃and —C(O)NR¹⁶R¹⁷; and

each R¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅alkyl.

In certain embodiments, with respect to the compounds of formula (H-IA),(H-IB), (H-IC), or (H-ID), each X¹, X² and X is independently CR⁶;wherein each R⁶ is independently halo, C₁-C₅-alkyl, halo C₁-C₈-alkyl,perhalo C₁-C₅-alkyl, or C₁-C₅-alkoxy. In certain embodiments, each X¹,X² and X is independently CR⁶; wherein each R⁶ is independently fluoro,chloro, methyl, ethyl, CF₃, or methoxy. In certain embodiments, U isCR⁶, wherein R⁶ is CF₃, methyl, chloro, CONHCH₃, COOH, COOCH₃, H, orfluoro; provided that R¹ is other than methyl.

In one embodiment, compounds of formula (H-IA-1), (H-IB-1), (H-IC-1) or(H-ID-1) are provided:

or a salt, solvate or N-oxide thereof, wherein:

U is N or CR⁶;

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl;

R⁶ is independently H, hydroxyl, halo, C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents independently selected from halo,hydroxyl, carboxyl and perhaloalkyl, optionally substituted C₁-C₅ alkoxyor optionally substituted —C(O)C₁-C₅ alkyl;

R⁷ is H, halo, optionally substituted C₁-C₅ alkyl, or optionallysubstituted aryl;

Q is aryl or heteroaryl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, C₁-C₅ alkyl,C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl, halo-substituted C₃-C₈cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy, cyano, carboxyl, —NHC(O)CH₃and —C(O)NR¹⁶R¹⁷; and

each R¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅alkyl.

In certain embodiments, with respect to the compounds of formula (H-IA),(H-IB), (H-IC) or (H-ID), (H-IA-1), (H-IB-1), (H-IC-1) or (H-ID-1), Q isan optionally substituted 5-membered heteroaryl; R⁷ is F or methyl; R¹is methyl; each X¹, X² and X (when present) is CR⁶, wherein each R⁶ isH; U is CR⁶, wherein R⁶ is methyl or Cl; and Q is other thanunsubstituted thienyl or unsubstituted thiazolyl.

In certain embodiments, with respect to the compounds of (H-IA), (H-IB),(H-IC) or (H-ID), (H-IA-1), (H-IB-1), (H-IC-1) or (H-ID-1), Q isoptionally substituted pyridyl; each X¹, X² and X (when present) is CR⁶,wherein each R⁶ is H; U is CR⁶, wherein R⁶ is H, halo, optionallysubstituted C₁-C₅ alkyl, or optionally substituted C₁-C₅ alkoxy; and Qis other than unsubstituted pyridyl, or pyridyl substituted with methyl,Cl, Br, OCH₃, or di-methyl.

In certain embodiments, with respect to the compounds of formula (H-IA),(H-IB), (H-IC) or (H-ID), (H-IA-1), (H-IB-1), (H-IC-1) or (H-ID-1), Q isoptionally substituted pyrimidinyl; R¹ is methyl; each X¹, X² and X(when present) is CR⁶, wherein each R⁶ is H; U is CR⁶, wherein R⁶ ismethyl or Cl; and Q is other than unsubstituted pyrimidin-4-yl,pyrimidin-4-yl substituted with methyl, unsubstituted pyrimidin-5-yl, orpyrimidin-5-yl substituted with methyl.

In certain embodiments, with respect to the compounds of formula(H-IA-1), the compound is Compound No. 99, 106, 222, 226-230, 232-235,238, 240-241, 244-249, or 251.

In certain embodiments, with respect to the compounds of formula(H-IB-1), the compound is Compound No. 224 or 239.

In certain embodiments, with respect to the compounds of formula(H-IC-1), Q is optionally substituted pyridyl, and the compound isCompound No. 78, 79, 100, 103, 105, 111, 112, 122, 124, 125, 126, 185,186, 188, 250, 257, 259, 266, 269, 312, 329, or 331.

In certain embodiments, with respect to the compounds of formula(H-IC-1), Q is optionally substituted pyrimidyl, and the compound isCompound No. 101, 187, or 279.

In certain embodiments, with respect to the compounds of formula(H-IC-1), Q is optionally substituted pyridyl, and the compound isCompound No. II-2, II-3, II-59, II-76, II-77, II-96, or II-101.

In certain embodiments, with respect to the compounds of formula(H-IC-1), Q is optionally substituted 5-membered heteroaryl, and thecompound is Compound No. 78, 108-110, 110, 115, 189, 273, 275, 277, 278,285, or 287.

In certain embodiments, with respect to the compounds of formula(H-IC-1), Q is optionally substituted 9-membered heteroaryl, and thecompound is Compound No. 282, 283, 284, 290, or 293.

In certain embodiments, with respect to the compounds of formula(H-IC-1), Q is optionally substituted quinolinyl or isoquinolinyl, andthe compound is Compound No. 292, 311, 316, or 323.

In certain embodiments, with respect to the compounds of formula (H-IC),X is N, and the compound is Compound No. 78, 124, or 335.

In certain embodiments, with respect to the compounds of formula(H-IE-1), the compound is Compound No. 193 or 194. In certainembodiments, with respect to the compounds of formula (H-IE-1), thecompound is Compound No. 193a, 193b, 194a, or 194b.

In certain embodiments, with respect to the compounds of formula(H-IF-1), the compound is Compound No. 199. In certain embodiments, withrespect to the compounds of formula (H-IF-1), the compound is CompoundNo. 199a or 199b.

In certain embodiments, with respect to the compounds of formula(H-IIB-1), the compound is Compound No. 333.

In certain embodiments, with respect to the compounds of formula(H-IIC-1), the compound is Compound No. 242, 256, 264, 313, 321, 328,330, or 334.

In certain embodiments, with respect to the compounds of formula(H-IID-1), the compound is Compound No. 95.

In certain embodiments, with respect to the compounds of formula(H-IA-1), (H-IB-1), (H—IC-1) or (H-ID-1) U is CR⁶, and R⁶ is CF₃,methyl, chloro, —CONHCH₃, —COOH, —COOCH₃, H, or fluoro; and R¹ is otherthan methyl.

In certain embodiments, with respect to the compounds of formula (H-IA),(H-IB), (H-IC) or (H-ID), (H-IA-1), (H-IB-1), (H-IC-1) or (H-ID-1), R⁷is H, halo, or C₁-C₅ alkyl substituted with halo. In one embodiment, R⁷is H, methyl, or CF₃.

In another aspect, provided is a compound of formula (J):

wherein:

R¹ is H; C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, hydroxyl,carboxyl, SO₃H, SR^(1a), S(O)R^(1a), SO₂R^(1a) and perhaloalkyl; C₃-C₈cycloalkyl optionally substituted with 1 to 3 substituents independentlyselected from the group consisting of halo, hydroxyl, carboxyl andperhaloalkyl; C₂-C₅ alkenyl optionally substituted with 1 to 3substituents independently selected from the group consisting of halo,hydroxyl, carboxyl and perhaloalkyl; or —C(O)O—C₁-C₅ alkyl; or is takentogether with R^(2a) or R^(3a) to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(4a)or R^(5a), where present, to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety;

R^(1a) is H or optionally substituted C₁-C₅ alkyl;

R^(2a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR¹ or R^(5a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety ora butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(3a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;or is taken together with R^(4a), where present, to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(3a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR¹ or R^(4a), where present, to form a propylene (—CH₂CH₂CH₂—) moiety ora butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R^(2a) toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety;or is taken together with R^(5a), where present, to form a methylene(—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

R^(4a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR^(3a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R¹ to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety; or istaken together with R^(2a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety; or is taken together with R^(5a), wherepresent, to form a methylene (—CH₂—) moiety;

R^(5a) is H; optionally substituted C₁-C₅ alkyl; optionally substitutedC₂-C₅ alkenyl; or optionally substituted aryl; or is taken together withR^(2a) to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R¹ to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety; or istaken together with R^(3a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety; or is taken together with R^(4a), wherepresent, to form a methylene (—CH₂—) moiety;

each R^(2b), R^(3b), R^(4b) and R^(5b) is independently H, optionallysubstituted C₁-C₅ alkyl, optionally substituted C₂-C₅ alkenyl, oroptionally substituted aryl;

each n and m is 1, or n is 0 and m is 1, or n is 1 and m is 0;

each X¹, X², X and U is independently N or CR⁶;

each R⁶ is independently H; hydroxyl; halo; C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxyl, carboxyl and perhaloalkyl; C₂-C₅alkenyl; optionally substituted C₁-C₅ alkoxy; or optionally substituted—C(O)C₁-C₅ alkyl;

Q is optionally substituted cycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl.

In one embodiment, compounds of formula (J-IA), (J-IB), (J-IC) or(J-ID):

or a salt, solvate or N-oxide thereof, wherein:

each X¹, X², X and U is independently N or CR⁶;

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl;

each R⁶ is independently H, hydroxyl, halo, C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents independently selected from halo,hydroxyl, carboxyl and perhaloalkyl, optionally substituted C₁-C₅ alkoxyor optionally substituted —C(O)C₁-C₅ alkyl;

Q is aryl or heteroaryl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, C₁-C₅ alkyl,C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl, halo-substituted C₃-C₈cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy, cyano, carboxyl, —NHC(O)CH₃and —C(O)NR¹⁶R¹⁷; and

each R¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅alkyl.

In certain embodiments, with respect to the compounds of formula (J-IA),(J-IB), (J-IC) or (J-ID), each X¹, X² and X is independently CR⁶;wherein each R⁶ is independently halo, C₁-C₅-alkyl, halo C₁-C₅-alkyl,perhalo C₁-C₅-alkyl, or C₁-C₅-alkoxy. In certain embodiments, each X¹,X² and X is independently CR⁶; wherein each R⁶ is independently fluoro,chloro, methyl, ethyl, CF₃, or methoxy. In certain embodiments, U isCR⁶, wherein R⁶ is CF₃, methyl, chloro, CONHCH₃, COOH, COOCH₃, H, orfluoro; provided that R¹ is other than methyl.

In certain embodiments, with respect to the compounds of formula (J-IA),(J-IB), (J-IC) or (J-ID), X is CR⁶, wherein R⁶ is fluoro; and R¹ isother than methyl.

In one embodiment, compound is according to formula (J-IA-1), (J-IB-1),(J-IC-1) or (J-ID-1) are provided:

or a salt, solvate or N-oxide thereof, wherein:

U is N or CR⁶;

R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,C₂-C₅ alkenyl optionally substituted with 1 to 3 substituentsindependently selected from halo, hydroxyl, carboxyl and perhaloalkyl,or —C(O)O—C₁-C₅ alkyl;

R⁶ is independently H, hydroxyl, halo, C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents independently selected from halo,hydroxyl, carboxyl and perhaloalkyl, optionally substituted C₁-C₅ alkoxyor optionally substituted —C(O)C₁-C₅ alkyl;

Q is aryl or heteroaryl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, C₁-C₅ alkyl,C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl, halo-substituted C₃-C₈cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy, cyano, carboxyl, —NHC(O)CH₃and —C(O)NR¹⁶R¹⁷; and

each R¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅alkyl.

In another embodiment, the compound is of the formula (K-IA), (K-IB),(K-IC) or (K-ID):

or a salt, solvate or N-oxide thereof, wherein:

X is N or CH;

R⁶ is C₁, CF₃, or methyl;

R⁷ is independently H or methyl;

R⁸ is H; azido; F; OH; NH₂; N(CH₃)H; N(CH₃)₂; NH-cyclopropyl; orNH-cyclobutyl; OC(O)N(CH₃)₂; or 3,3-dimethyl-2-hydroxybutyl; and

Q is unsubstituted 3-pyridyl; 3-pyridyl substituted with methyl, Cl, orCONH₂; unsubstituted 4-pyridyl; 4-pyridyl substituted with OH;unsubstituted pyrazinyl; unsubstituted imidazolyl; or unsubstitutedtriazolyl.

In certain embodiments, with respect to the compounds of formula (K-IA),(K-IB), (K-IC) or (K-ID); R⁷ is H, and R⁸ is OH. In one embodiment, thecompound is Compound No. 3, 4, 13, 39, 41, 129, or 144 (Table I); orII-132, II-138, II-139, or II-140 (Table II).

In certain embodiments, with respect to the compounds of formula (K-IA),(K-IB), (K-IC) or (K-ID); R⁷ is methyl, and R⁸ is OH. In one embodiment,the compound is Compound No. 5, 14, 26, 29, 31, 148, 173, 174, or 176(Table I); or II-148 (Table II).

In certain embodiments, with respect to the compounds of formula (K-IA),(K-IB), (K-IC) or (K-ID); R⁸ is NH₂, N(CH₃)H, N(CH₃)₂, NH-cyclopropyl,or NH-cyclobutyl. In one embodiment, the compound is Compound No. 27,150, 151, or 154 (Table I); or II-4, II-7, II-13, or II-260 (Table II).

In certain embodiments, with respect to the compounds of formula (K-IA),(K-IB), (K-IC) or (K-ID); each R⁷ and R⁸ is H. In one embodiment, thecompound is Compound 74, 134, or II-244 (Table I and II).

In certain embodiments, with respect to the compounds of formula (K-IA),(K-IB), (K-IC) or (K-ID); R⁷Me, and R⁸ is F. In one embodiment, thecompound is Compound II-212 (Table II).

In certain embodiments, with respect to the compounds of formula (K-IA),(K-IB), (K-IC) or (K-ID); R⁸ is —OC(O)N(CH₃)₂. In one embodiment, thecompound is Compound No. 141.

In certain embodiments, with respect to the compounds of formula (K-IA),(K-IB), (K-IC) or (K-ID); R⁷ is 3,3-dimethyl-2-hydroxybutyl. In oneembodiment, the compound is Compound II-227 (Table II).

In another embodiment, the compound is of the formula (K-IE), or (K-IF):

or a salt, solvate or N-oxide thereof, wherein:

R⁶ is Cl, or methyl;

R⁷ is H or methyl;

R⁸ is OH; N(CH₃)₂; or OC(O)-t-Bu;

and

Q is phenyl substituted with F; unsubstituted 3-pyridyl; 3-pyridylsubstituted with methyl; unsubstituted 4-pyridyl; or unsubstitutedpyrazinyl.

In certain embodiments, with respect to the compounds of formula (K-IE),or (K-IF); R⁷ is H, and R⁸ is OH. In one embodiment, the compound isCompound No. 129 (Table I); or II-131 (Table II).

In certain embodiments, with respect to the compounds of formula (K-IE),or (K-IF); R⁷ is methyl, and R⁸ is OH. In one embodiment, the compoundis II-121, II-127, II-128, or II-130 (Table II).

In certain embodiments, with respect to the compounds of formula (K-IE),or (K-IF); N(CH₃)₂. In one embodiment, the compound is Compound II-6(Table II).

In one embodiment, the compound is Compound II-123 (Table II).

In one embodiment, the compound is Compound No. 325 (Table I).

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), (A-IIIE-6), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or(C-IA-5), and R¹ is methyl.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), (A-IIIE-6), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or(C-IA-5), and R⁶ is methyl, chloro, or trifluoromethyl.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), (A-IIIE-6), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or(C-IA-5), and R⁷ is H, methyl, cyclopropyl, cyclobutyl, or3,3-dimethyl-2-hydroxybutyl.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), (A-IIIE-6), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or(C-IA-5), and R⁸ is H, F, OH, —N(CH₃)₂, or —OC(O)N(CH₃)₂.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or (C-IA-5),and Y² is N. In one embodiment, Y² is N, and one of Y¹, Y³, or Y⁴ ismethyl.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or (C-IA-5),and Y³ is N. In one embodiment, Y³ is N, and one of Y¹, Y², or Y⁴ ismethyl.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or (C-IA-5),and each of Y¹ and Y⁴ is N.

In certain embodiments, with respect to the compounds of formula(A-IIIE-6), and Q is triazolyl, or imidazolyl.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), (A-IIIE-6), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or(C-IA-5), R⁷ is H, R⁸ is OH, and the compound is Compound No. 3, 4, 13,39, 41, 127, 144, II-132, II-138, II-139, or II-140.

In certain embodiments, with respect to the compounds of formula (I),(A-IIIE-2), (A-IIIE-6), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or(C-IA-5), R⁷ is methyl, R⁸ is OH, and the compound is Compound No. 5,14, 26, 29, 31, 148, 173, 174, 176, II-148, II-151, II-152, or II-220.

In certain embodiments, with respect to the compounds of formula (I),(A-IIIE-2), (A-IIIE-6), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or(C-IA-5), R⁸ is NH₂, N(CH₃)H, N(CH₃)₂, NH— cyclopropyl, orNH-cyclobutyl, and the compound is Compound No. 27, 150, 151, 154, II-4,II-7, II-13, or II-260.

In certain embodiments, with respect to the compounds of formula (I),(A-IIIE-2), (A-IIIE-6), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or(C-IA-5), each R⁷ and R⁸ is H, and the compound is Compound No. 74, 134,or II-244.

In certain embodiments, with respect to the compounds of formula (I),(A-IIIE-2), (A-IIIE-6), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or(C-IA-5), R⁷Me, and R⁸ is F, and the compound is Compound No. II-212.

In certain embodiments, with respect to the compounds of formula (I),(A-IIIE-2), (A-IIIE-6), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or(C-IA-5), R⁸ is —OC(O)N(CH₃)₂, and the compound is Compound No. 141.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2), (A-IIIE-6), (A-IIIF-2), (A-IIIG-2), (A-IIIH-2), (C-IA-4), or(C-IA-5), and R⁷ is 3,3-dimethyl-2-hydroxybutyl, and the compound isCompound No. II-227.

In one embodiment, with respect to the compounds of formula (A-IB),(A-IC), (A-ID), (A-IE), (A-VIIIA), (A-VIIIB), (C-VA), (C-VB), (D-IIIA),(D-IIIB), (H-IA), (H-IB), (H-IC) or (H-ID), (H-IA-1), (H-IB-1),(H-IC-1), (H-ID-1), (J-IA), (J-IB), (J-IC) or (J-ID), (J-IA-1),(J-IB-1), (J-IC-1) or (J-ID-1), Q is optionally substituted phenyl.

In one embodiment, with respect to the compounds of formula (A-IB),(A-IC), (A-ID), (A-IE), (A-VIIIA), (A-VIIIB), (C-VA), (C-VB), (D-IIIA),(D-IIIB), (H-IA), (H-IB), (H-IC) or (H-ID), (H-IA-1), (H-IB-1),(H-IC-1), (H-ID-1), (J-IA), (J-IB), (J-IC) or (J-ID), (J-IA-1),(J-IB-1), (J-IC-1) or (J-ID-1), Q is phenyl substituted with C₁-C₅alkyl, halo, halo C₁-C₅ alkyl, or C₁-C₅ alkoxy.

In one embodiment, with respect to the compounds of formula (A-IB),(A-IC), (A-ID), (A-IE), (A-VIIIA), (A-VIIIB), (C-VA), (C-VB), (D-IIIA),(D-IIIB), (H-IA), (H-IB), (H-IC) or (H-ID), (H-IA-1), (H-IB-1),(H-IC-1), (H-ID-1), (J-IA), (J-IB), (J-IC) or (J-ID), (J-IA-1),(J-IB-1), (J-IC-1) or (J-ID-1), Q is phenyl substituted with methyl,ethyl, F, Cl, OCH₃, or CF₃.

In one embodiment, with respect to the compounds of formula (A-IB),(A-IC), (A-ID), (A-IE), (A-VIIIA), (A-VIIIB), (C-VA), (C-VB), (D-IIIA),(D-IIIB), (H-IA), (H-IB), (H-IC) or (H-ID), (H-IA-1), (H-IB-1),(H-IC-1), (H-ID-1), (J-IA), (J-IB), (J-IC) or (J-ID), (J-IA-1),(J-IB-1), (J-IC-1) or (J-ID-1), Q is optionally substituted pyridyl, oroptionally substituted pyrimidinyl.

In one embodiment, with respect to the compounds of formula (A-IB),(A-IC), (A-ID), (A-IE), (A-VIIIA), (A-VIIIB), (C-VA), (C-VB), (D-IIIA),(D-IIIB), (H-IA), (H-IB), (H-IC) or (H-ID), (H-IA-1), (H-IB-1),(H-IC-1), (H-ID-1), (J-IA), (H-IIB, (J-IC) or (J-ID), (J-IA-1),(J-IB-1), (J-IC-1) or (J-ID-1), Q is pyridyl substituted with C₁-C₅alkyl, halo, halo or C₁-C₅ alkyl.

In one embodiment, with respect to the compounds of formula (A-IB),(A-IC), (A-ID), (A-IE), (A-VIIIA), (A-VIIIB), (C-VA), (C-VB), (D-IIIA),(D-IIIB), (H-IA), (H-IB), (H-IC) or (H-ID), (H-IA-1), (H-IB-1),(H-IC-1), (H-ID-1), (J-IA), (J-IB), (J-IC) or (J-ID), (J-IA-1),(J-IB-1), (J-IC-1) or -1), Q is pyridyl substituted with methyl, ethyl,F, Cl, or CF₃.

In one embodiment, with respect to the compounds of formula (A-IB),(A-IC), (A-ID), (A-IE), (A-VIIIA), (A-VIIIB), (C-VA), (C-VB), (D-IIIA),(D-IIIB), (H-IA), (H-IB), (H-IC) or (H-ID), (H-IA-1), (H-IB-1),(H-IC-1), (H-ID-1), (J-IA), (J-IB), (J-IC) or (J-ID), (J-IA-1),(J-IB-1), (J-IC-1) or (J-ID-1), R¹ is H; unsubstituted C₁-C₅ alkyl;C₁-C₅ alkyl substituted with OH or SO₃H; cycloalkyl; or C₂-C₅ alkenyl.

In one embodiment, with respect to the compounds of formula (A-IB),(A-IC), (A-ID), (A-IE), (A-VIIIA), (A-VIIIB), (C-VA), (C-VB), (D-IIIA),(D-IIIB), (H-IA), (H-IB), (H-IC) or (H-ID), (H-IA-1), (H-IB-1),(H-IC-1), (H-ID-1), (J-IA), (J-IB), (J-IC) or (J-ID), (J-IA-1),(J-IB-1), (J-IC-1) or (J-ID-1), R¹ is H; unsubstituted C₁-C₅ alkyl;C₁-C₅ alkyl substituted with up to three halogen atoms; cycloalkyl; orC₂-C₅ alkenyl.

In one embodiment, with respect to the compounds of formula (A-IB),(A-IC), (A-ID), (A-IE), (A-VIIIA), (A-VIIIB), (C-VA), (C-VB), (D-IIIA),(D-IIIB), (H-IA), (H-IB), (H-IC) or (H-ID), (H-IA-1), (H-IB-1),(H-IC-1), (H-ID-1), (J-IA), (J-IB), (J-IC) or (J-ID), (J-IA-1),(J-IB-1), (J-IC-1) or (J-ID-1), R¹ is methyl, ethyl, hydroxyethyl,hydroxypropyl, hydroxybutyl, cyclobutyl, cyclopropyl, CF₃, CH₂CF₃ orCH₂CH₂—SO₃H.

In one particular embodiment, with respect to the compounds of formula(A-IB), (A-IC), (A-ID), (A-IE), (A-VIIIA), (A-VIIIB), (C-VA), (C-VB),(D-IIIA), (D-IIIB), (H-IA), (H-IB), (H-IC) or (H-ID), (H-IA-1),(H-IB-1), (H-IC-1), (H-ID-1), (J-IA), (J-IB), (J-IC) or (J-ID),(J-IA-1), (J-IB-1), (J-IC-1) or (J-ID-1), R¹ is methyl.

In one embodiment, with respect to the compounds of formula (I); R^(4a)is F. In another embodiment, each R^(4a) and R^(4b) is F. In aparticular embodiment, the compound is Compound II-267 or II-280.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2); when R¹ is methyl, R^(4a) is F, R^(4b) is H, R⁶ is Cl, eachR⁷ and R⁸ is H, and Y³ is C—CF₃; then Y² is other than N.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2); when R¹ is methyl, each R^(4a) and R^(4b) is F, H, R⁶ ismethyl, each R⁷ and R⁸ is H, and Y³ is C—CH₃; then Y² is other than N.

In certain embodiments, with respect to the compounds of formula(A-IIIE-2); when R¹ is methyl, each R^(4a) and R^(4b) is F, H, R⁶ is Clor methyl, each R⁷ and R⁸ is H, and Y³ is C—F; then Y² is other than CH.

In one embodiment, the invention relates to Compound No. 87, and usesthereof. In another embodiment, the invention relates to Compound No.88, and uses thereof. In yet another embodiment, the invention relatesto Compound No. 120, and uses thereof. In a further embodiment, theinvention relates to Compound No. 324, and uses thereof.

In one embodiment, the invention relates to Compound No. 338, and usesthereof. In another embodiment, the invention relates to Compound No.II-1, and uses thereof.

In another embodiment, the invention relates to Compound No. 129d anduses thereof.

In one embodiment, the invention relates to Compound Nos. 325, 129d,130a, II-121b, II-123b, II-127a, II-128b, II-130a, II-131, and II-6b,and uses thereof.

In one embodiment, the invention relates to Compound Nos. 18, 18a, 18b,30a, 30b, 54, 54a, 54b, 90a, 90b, 129, 129a, 129b, 129c, 129d, 130,130a, 130b, 142, 142a, 142b, 168, 168a, 168b, 168c, 168d, 169, 169a,169b, 179, 179a, 179b, 183a, 183b, 187, 188, 189, 190, 191, 193, 193a,193b, 194a, 194b, 196a, 196b, 197, 197a, 197b, 198, 198a, 198b, 199a,199b, 203a, 203b, 269, 270, 271, 272a, 272b, 273, 274, 274a, 274b, 275,276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288a, 288b,289a, 289b, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301,302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 314a,314b, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327,328, 329, 330, 331, 332, 333, 334, 335, 336, 336a, 336b, 338, 338, 338a,338b, 339, 339a, 339b.

In another embodiment, the invention relates to Compounds 3, 3b, 4a, 5band 39a. In another embodiment, the invention relates to Compounds 3,3a, 3b, 5, 5a, 5b, 13b, 14a, 15b, 26a, 26b, 27a, 29a, 31a, 74a, 93a,127a, 130a, 130b, 133b, 134b, 137a, 139a, 141, 144b, 147, 150a and 154,and uses thereof.

In another embodiment, the invention relates to Compound Nos. 3, 39, 4,5, 13, 14, 41, 74, 26, 27, 29, 31, 127, 129, 134, 144, 148, 173, 174,150, 176, IV-210, 151, II-4, II-132, 141, 154, II-135, II-138, II-139,II-140, V-22, II-244, II-7, II-146, II-151, II-152, II-227, II-220,II-148, II-13, II-212, II-260 and II-260b, and uses thereof. In anotherembodiment, the invention relates to Compound Nos. 3a, 3b, 39a, 4a, 5b,13b, 14a, 41a, 74a, 26a, 26b, 27a, 29b, 31a, 127a, 129d, 134b, 144b,148, 173a, 174a, 150a, 176a, IV-210a, 151a, II-4-b, II-132b, 148b, 141b,154b, II-135b, II-138, II-139, II-140, V-22, II-244a, II-7, II-146a,II-15b, II-152a, II-227c, II-220, II-148a, II-13a, II-212a, II-260a andII-260b, and uses thereof.

In one embodiment, the invention relates to Compound Nos. 3a, 3b, 4a,4b, 5a, 5b, 6, 7a, 7b, 8a, 8b, 9, 9a, 9b, 10, 10a, 10b, 11, 11a, 11b,12, 12a, 12b, 13a, 13b, 14, 14a, 14b, 15a, 15b, 16, 16a, 16b, 17, 17a,17b, 18, 18a, 18b, 19, 19a, 19b, 20, 20a, 20b, 21, 21a, 21b, 22a, 22b,23, 23a, 23b, 24, 24a, 24b, 25, 25a, 25b, 26, 26a, 26b, 26c, 26d, 27,27a, 27b, 28, 28a, 28b, 29a, 29b, 30a, 30b, 31a, 31b, 36, 37, 37c, 37d,39, 39a, 39b, 40, 40a, 40b, 41, 41a, 41b, 42, 42a, 42b, 43a, 43b, 44,44a, 44b, 45, 45a, 45b, 47a, 47b, 47c, 47d, 48a, 48b, 49a, 49b, 51, 51a,51b, 52, 52a, 52b, 53, 53a, 53b, 54, 54, 54a, 54b, 55, 55a, 55b, 56,56a, 56b, 57, 57a, 57b, 58, 58a, 58b, 59, 59a, 59b, 63, 63a, 63b, 64,65, 66, 67, 68, 69, 69a, 69b, 70, 71, 72, 75, 75a, 75b, 75c, 75d, 76,76a, 76b, 76c, 76d, 77, 78, 79, 80, 81, 82, 90a, 90b, 108, 109, 110,111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 124, 125,126, 127, 127a, 127b, 128a, 128b, 129a, 129b, 129c, 129d, 130a, 130b,131a, 131b, 133a, 133b, 134a, 134b, 135a, 135b, 136a, 136b, 137a, 137b,138a, 138b, 139, 139a, 139b, 140, 140a, 140b, 141, 141a, 141b, 142,142a, 142b, 143, 143a, 143b, 144, 144a, 144b, 145, 146, 146a, 146b, 147,147a, 147b, 148, 148a, 148b, 148c, 148d, 149, 149a, 149b, 150, 150a,150b, 151, 151a, 151b, 152, 152a, 152b, 153, 154, 154a, 154b, 155, 155a,155b, 156, 157, 158, 159, 159a, 159b, 160, 160a, 160b, 168, 169, 170,171, 172a, 172b, 173, 173a, 173b, 174, 174a, 174b, 175, 175a, 175b, 176,176a, 176b, 177, 178, 179, 189, 190, 191, 193, 193a, 193b, 194a, 194b,196, 196a, 196b, 197, 197a, 197b, 198, 198a, 198b, 198c, 198d, 199a,199b, 203a, 203b, 211a, 211b, 221a, 221b, 223a, 223b, 225a, 225b, 231a,231b, 253a, 253b, 255a, 255b, 257a, 257b, 269, 270, 271, 272a, 272b,273, 274, 274a, 274b, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284,285, 286, 287, 288a, 288b, 289a, 289b, 290, 291, 292, 293, 294, 295,296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309,310, 311, 312, 313, 314, 314a, 314b, 315, 316, 317, 318, 319, 320, 321,322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335,336, 336a, 336b, 338, 338a, 338b, 339a, 339b, II-1a, II-1b, II-2, II-3,II-4-a, II-4-b, II-5, II-6a, II-6b, II-7, II-7a, II-7b, II-8, II-9,II-10, II-11, II-11a, II-11b, II-12, II-12a, II-12b, II-13, II-13a,II-13b, II-14a, II-14b, II-15a, II-15b, II-16a, II-16b, II-17, II-18,II-19, II-39, II-40, II-49a, II-49b, II-57a, II-57b, II-58, II-59,II-60, II-61, II-62, II-63, II-64, II-65, II-67, II-68, II-70, II-71,II-75, II-76, II-77, II-78, II-80, II-81, II-82, II-83, II-84, II-88,II-89, II-90, II-91, II-92, II-93a, II-93b, II-94a, II-94b, II-95a,II-95b, II-96, II-97, II-98a, II-98b, II-99a, II-99b, II-100a, II-100b,II-101, II-102, II-103, II-104, II-105, II-106a, II-106b, II-108a,II-108b, II-109a, II-109b, II-110, II-111, II-112a, II-112b, II-113a,II-113b, II-114a, II-114b, II-115a, II-115b, II-115c, II-115d, II-116,II-117, II-118a, II-118b, II-119, II-120a, II-120b, II-121a, II-121b,II-122, II-123a, II-123b, II-124a, II-124b, II-125a, II-125b, II-125c,II-125d, II-126, II-127a, II-127b, II-128a, II-128b, II-129, II-130,II-130a, II-130b, II-131, II-132a, II-132b, II-133, II-134a, II-134b,II-135a, II-135b, II-136a, II-136b, II-137, II-138, II-139, II-140,II-141, II-142, II-143, II-144, II-145, II-146a, II-146b, II-146c,II-146d, II-147a, II-147b, II-147c, II-147d, II-148, II-148a, II-148b,II-149a, II-149b, II-149c, II-149d, II-150, II-151a, II-15b, II-152a,II-152b, II-152c, II-152d, II-153, II-154, II-209, II-210, II-211,II-212, II-212a, II-212b, II-213, II-215, II-220, II-221, II-222,II-223, II-224, II-224a, II-224b, II-225, II-226, II-227a, II-227b,II-227c, II-227d, II-229, II-230, II-231, II-232, II-240, II-241,II-242, II-243, II-244a, II-244b, II-245, II-246, II-247, II-248,II-249, II-250, II-251, II-252, II-253, II-255a, II-255b, II-256,II-257, II-258, II-259, II-260a, II-260b, II-261, II-261a, II-261b,II-262, II-263, II-264, II-265a, II-265b, II-266, II-267, II-268,II-269, II-270, II-271, II-272, II-273, II-274, II-275, II-276, II-277,II-278, II-279, II-280, II-281, II-282a, II-282b, II-282c, II-282d,II-283, II-284, II-285, II-286, II-287, II-288, II-289, II-290a,II-290b, II-291a, II-291b, II-291c, II-291d, II-292, II-293a, II-293b,II-293c, II-293d, II-294a, II-294b, II-294c, II-294d, II-295, II-296a,II-296b, II-297, II-298, II-299, IV-8, IV-8a, IV-8b, IV-93a, IV-93b,IV-209a, IV-209b, IV-209c, IV-209d, IV-210a, IV-210b, IV-210c, IV-210d,V-1, V-1a, V-1b, V-2, V-2a, V-2b, V-3, V-3a, V-3b, V-14, V-14a, V-14b,V-15, V-15a, V-15b, V-15c, V-15d, V-18, V-18a, V-18b, V-18c, V-18d,V-21, V-21a, V-21b, V-22, V-22a, V-22b, V-23, V-23a and V-23b.

In another embodiment, the invention relates to Compounds described inTable 1, and uses thereof. In another embodiment, the invention relatesto one or more of the Compounds described in Table 2, and uses thereof.

In another embodiment, the invention relates to one or more of theCompounds described in Table 3, and uses thereof.

In another embodiment, the invention relates to one or more of theCompounds described in Table 4, and uses thereof.

In another embodiment, the invention relates to one or more of theCompounds described in Table 5, and uses thereof.

In one embodiment, the invention embraces compounds detailed hereinprovided that the compound is other than dimebon and metabolites ofdimebon. In another embodiment, the invention embraces dimebon or a saltthereof for uses detailed herein. In another embodiment, the inventionembraces a dimebon metabolite or salt thereof for uses detailed herein,such as use in therapy, e.g., to increase insulin secretion and treatdiseases or conditions that are, or are expected to be, responsive to anincrease in insulin production, or to treat type 2 diabetes.

The embodiments and variations described herein are suitable forcompounds of any formulae detailed herein, where applicable.

Representative examples of compounds detailed herein, includingintermediates and final compounds according to the invention aredepicted in the tables below. It is understood that in one aspect, anyof the compounds may be used in the methods detailed herein, including,where applicable, intermediate compounds that may be isolated andadministered to an individual.

The compounds depicted herein may be present as salts even if salts arenot depicted and it is understood that the invention embraces all saltsand solvates of the compounds depicted here, as well as the non-salt andnon-solvate form of the compound, as is well understood by the skilledartisan. In some embodiments, the salts of the compounds of theinvention are pharmaceutically acceptable salts. Where one or moretertiary amine moiety is present in the compound, the N-oxides are alsoprovided and described.

Where tautomeric forms may be present for any of the compounds describedherein, each and every tautomeric form is intended even though only oneor some of the tautomeric forms may be explicitly depicted. For example,when a 2-hydroxypyridyl moiety is depicted, the corresponding 2-pyridonetautomer is also intended. The tautomeric forms specifically depictedmay or may not be the predominant forms in solution or when usedaccording to the methods described herein.

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. In one aspect, the pharmaceuticallyacceptable salt is an acid addition salt, such as a salt formed with aninorganic or organic acid. Pharmaceutical compositions according to theinvention may take a form suitable for oral, buccal, parenteral, nasal,topical or rectal administration or a form suitable for administrationby inhalation.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. In onevariation, “substantially pure” intends a composition that contains nomore than 35% impurity, wherein the impurity denotes a compound otherthan the compound comprising the majority of the composition or a saltthereof. Taking compound 1 as an example, a composition of substantiallypure compound 1 intends a composition that contains no more than 35%impurity, wherein the impurity denotes a compound other than compound 1or a salt thereof. In one variation, a composition of substantially purecompound or a salt thereof is provided wherein the composition containsno more than 25% impurity. In another variation, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains or no more than 20% impurity. In still anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 10%impurity. In a further variation, a composition of substantially purecompound or a salt thereof is provided wherein the composition containsor no more than 5% impurity. In another variation, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains or no more than 3% impurity. In still anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 1%impurity. In a further variation, a composition of substantially purecompound or a salt thereof is provided wherein the composition containsor no more than 0.5% impurity.

In one variation, the compounds herein are synthetic compounds preparedfor administration to an individual. In another variation, compositionsare provided containing a compound in substantially pure form. Inanother variation, the invention embraces pharmaceutical compositionscomprising a compound detailed herein and a pharmaceutically acceptablecarrier. In another variation, methods of administering a compound areprovided. The purified forms, pharmaceutical compositions and methods ofadministering the compounds are suitable for any compound or formthereof detailed herein.

Kits comprising a compound of the invention, or a salt or solvatethereof, and suitable packaging are provided. In one embodiment, a kitfurther comprises instructions for use. In one aspect, a kit comprises acompound of the invention, or a salt or solvate thereof, andinstructions for use of the compounds in the treatment of a disease orindication for which enhancing insulin secretion and/or promotinginsulin release is expected to be or is beneficial.

Articles of manufacture comprising a compound of the invention, or asalt or solvate thereof, in a suitable container are provided. Thecontainer may be a vial, jar, ampoule, preloaded syringe, i.v. bag, andthe like.

In one aspect, an adrenergic receptor α_(2A) antagonist as providedherein exhibits the ability to cross the blood-brain barrier. In anotheraspect, an adrenergic receptor α_(2A) antagonist as provided herein isnot able to cross the blood-brain barrier. In one aspect, an adrenergicreceptor α_(2A) antagonist as provided herein exerts its therapeuticeffect in the brain only. In one aspect, an adrenergic receptor α_(2A)antagonist as provided herein exerts its therapeutic effect in theperiphery only. In one aspect, an adrenergic receptor α_(2A) antagonistas provided herein exerts its therapeutic effect both in the brain andperipherally. In some embodiments, the adrenergic receptor α_(2A)antagonist also exhibits adrenergic receptor α_(2A) inverse agonistactivity.

Blood brain barrier permeability can be measured in rodents or dog byadministering the compound orally or intravenously, recovering a bloodand brain tissue sample at different time points and comparing how muchcompound is in each sample. Blood fraction is typically processed toplasma for determination of compound content. Brain exposure can bedescribed from the ratio of brain to plasma levels of drug. In onevariation, a compound that poorly crosses the blood brain barrier has abrain to plasma ratio of compound of about 0.1 or less. In anothervariation, the compound has a brain to plasma ratio of about 0.2 orless, about 0.3 or less, about 0.4 or less, about 0.5 or less, about 0.8or less, or about 1.0 or less.

Preferably, the compounds provided herein are orally bioavailable.However, the compounds may also be formulated for parenteral (e.g.,intravenous) administration. In some settings, parenteral administrationmay be desired.

One or several compounds described herein can be used in the preparationof a medicament by combining the compound or compounds as an activeingredient with a pharmaceutically acceptable carrier, which are knownin the art. Depending on the therapeutic form of the medication, thecarrier may be in various forms. In one variation, the manufacture of amedicament is for use in any of the methods disclosed herein, e.g.,increasing insulin secretion of an individual or treating or delayingthe onset and/or development of type 2 diabetes, glucose intolerance ormetabolic syndrome.

Methods as provided herein may comprise administering to an individual apharmacological composition that contains an effective amount of acompound and a pharmaceutically acceptable carrier. The effective amountof the compound may in one aspect be a dose of between about 0.01 andabout 100 mg.

The compound may be formulated for any available delivery route,including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal orrectal), parenteral (e.g., intramuscular, subcutaneous or intravenous),topical or transdermal delivery form. A compound may be formulated withsuitable carriers to provide delivery forms that include, but are notlimited to, tablets, caplets, capsules (such as hard gelatin capsules orsoft elastic gelatin capsules), cachets, troches, lozenges, gums,dispersions, suppositories, ointments, cataplasms (poultices), pastes,powders, dressings, creams, solutions, patches, aerosols (e.g., nasalspray or inhalers), gels, suspensions (e.g., aqueous or non-aqueousliquid suspensions, oil-in-water emulsions or water-in-oil liquidemulsions), solutions and elixirs.

One or several compounds described herein can be used in the preparationof a formulation, such as a pharmaceutical formulation, by combining thecompound or compounds as an active ingredient with a pharmaceuticallyacceptable carrier, such as those mentioned above. Depending on thetherapeutic form of the system (e.g., transdermal patch vs. oraltablet), the carrier may be in various forms. In addition,pharmaceutical formulations may contain preservatives, solubilizers,stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters,salts for the adjustment of osmotic pressure, buffers, coating agents orantioxidants. Formulations comprising the compound may also containother substances which have valuable therapeutic properties.Pharmaceutical formulations may be prepared by known pharmaceuticalmethods. Suitable formulations can be found, e.g., in Remington'sPharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa.,20^(th) ed. (2000), which is incorporated herein by reference.

Compounds as described herein may be administered to individuals in aform of generally accepted oral compositions, such as tablets, coatedtablets, gel capsules in a hard or in soft shell, emulsions orsuspensions. Examples of carriers, which may be used for the preparationof such compositions, are lactose, corn starch or its derivatives, talc,stearate or its salts, etc. Acceptable carriers for gel capsules withsoft shell are, for instance, plant oils, wax, fats, semisolid andliquid poly-ols, and so on. In addition, pharmaceutical formulations maycontain preservatives, solubilizers, stabilizers, re-wetting agents,emulgators, sweeteners, dyes, adjusters, salts for the adjustment ofosmotic pressure, buffers, coating agents or antioxidants.

Any of the compounds described herein can be formulated in a tablet inany dosage form described, for example, a compound as described hereinor a pharmaceutically acceptable salt thereof can be formulated as a 10mg tablet.

The compound may be administered to an individual in accordance with aneffective dosing regimen for a desired period of time or duration, suchas at least about one month, at least about 2 months, at least about 3months, at least about 6 months, or at least about 12 months or longer,which in some variations may be for the duration of the individual'slife. In one variation, the compound is administered on a daily orintermittent schedule. The compound can be administered to an individualcontinuously (for example, at least once daily) over a period of time.The dosing frequency can also be less than once daily, e.g., about aonce weekly dosing. The dosing frequency can be more than once daily,e.g., twice or three times daily. The dosing frequency can also beintermittent (e.g., once daily dosing for 7 days followed by no dosesfor 7 days, repeated for any 14 day time period, such as about 2 months,about 4 months, about 6 months or more). Any of the dosing frequenciescan employ any of the compounds described herein together with any ofthe dosages described herein.

Compositions comprising a compound provided herein are also described.In one variation, the composition comprises a compound and apharmaceutically acceptable carrier or excipient. In another variation,a composition of substantially pure compound is provided.

The invention further provides kits for carrying out the methods of theinvention, which comprises one or more compounds described herein or apharmacological composition comprising a compound described herein. Thekits may employ any of the compounds disclosed herein. In one variation,the kit employs a compound described herein or a pharmaceuticallyacceptable salt thereof. The kits may be used for any one or more of theuses described herein, and, accordingly, may contain instructions forany one or more of the following uses: treating, preventing, and/ordelaying the onset and/or development of diabetes type 2 and/or adisease or condition which is responsive, or expected to be responsive,to an increase in insulin secretion.

Kits generally comprise suitable packaging. The kits may comprise one ormore containers comprising any compound described herein. Each component(if there is more than one component) can be packaged in separatecontainers or some components can be combined in one container wherecross-reactivity and shelf life permit.

The kits may be in unit dosage forms, bulk packages (e.g., multi-dosepackages) or sub-unit doses. For example, kits may be provided thatcontain sufficient dosages of a compound as disclosed herein and/or asecond pharmaceutically active compound useful for a disease detailedherein (e.g., type 2 diabetes) to provide effective treatment of anindividual for an extended period, such as any of a week, 2 weeks, 3weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7months, 8 months, 9 months, or more. Kits may also include multiple unitdoses of the compounds and instructions for use and be packaged inquantities sufficient for storage and use in pharmacies (e.g., hospitalpharmacies and compounding pharmacies).

The kits may optionally include a set of instructions, generally writteninstructions, although electronic storage media (e.g., magnetic disketteor optical disk) containing instructions are also acceptable, relatingto the use of component(s) of the methods of the present invention. Theinstructions included with the kit generally include information as tothe components and their administration to an individual.

The invention also provides compositions (including pharmacologicalcompositions) as described herein for the use in treating, preventing,and/or delaying the onset and/or development of diabetes type 2 and/or adisease or condition which is responsive, or expected to be responsive,to an increase in insulin secretion and other methods described herein.In certain embodiments, the composition comprises a pharmaceuticalformulation which is present in a unit dosage form. As used herein, theterm “unit dosage form” refers to a formulation that contains apredetermined dose of a compound as disclosed herein and optionally asecond pharmaceutically active compound useful for treatment of adisease or condition detailed herein (e.g., type 2 diabetes).

For compounds bearing one or more chiral centers, each uniquestereoisomer has a compound number bearing a suffix “a”, “b”, etc. Asexamples, racemic compound V-1, bearing one chiral center, can beresolved into its individual enantiomers V-1a and V-1b.

Similarly, racemic compound V-4, bearing two chiral centers, can beresolved into its individual diastereomers V-4-a, V-4-b, V-4-c andV-4-d.

Representative compounds of the invention are shown in Tables 1-5.

TABLE 1 Representative Compounds of the Invention

1 1a, 1b

2 2a, 2b

3 3a, 3b

4 4a, 4b

5 5a, 5b

6 6a, 6b

7 7a, 7b

8 8a, 8b

9 9a, 9b

10 10a, 10b

11 11a, 11b

12 12a, 12b

13 13a, 13b

14 14a, 14b

15 15a, 15b

16 16a, 16b

17 17a, 17b

18 18a, 18b

19 19a, 19b

20 20a, 20b

21 21a, 21b

22 22a, 22b

23 23a, 23b

24 24a, 24b

25 25a, 25b 25c, 25d

26 26a, 26b 26c, 26d

27 27a, 27b

28 28a, 28b

29 29a, 29b

30 30a, 30b

31 31a, 31b

32 32a, 32b

33 33a, 33b

34 34a, 34b

35 35a, 35b

36 36a, 36b, 36c, 36d

37 37a, 37b 37c, 37d

38 38a, 38b, 38c, 38d, 38e, 38f, 38g, 38h

39 39a, 39b

40 40a, 40b

41 41a, 41b

42 42a, 42b

43 43a, 43b

44 44a, 44b

45 45a, 45b

46 46a, 46b

47 47a, 47b, 47c, 47d

48 48a, 48b

49 49a, 49b

50 50a, 50b, 50c, 50d

51 51a, 51b

52 52a, 52b

53 53a, 53b

54 54a, 54b

55 55a, 55b

56 56a, 56b

57 57a, 57b

58 58a, 58b

59 59a, 59b

60

61

62 62a, 62b

63 63a, 63b

64 64a, 64b

65 65a, 65b

66 66a, 66b

67 67a, 67b

68

69 69a, 69b

70 70a, 70b, 70c, 70d

71 71a, 71b

72 72a, 72b

73 73a, 73b, 73c, 73d

74 74a, 74b

75 75a, 75b, 75c, 75d

76 76a, 76b, 76c, 76d

77

78

79

80

81 81a, 81b

82 82a, 82b

83

84

85

86

87

88

89

90 90a, 90b

91

92

93 93a, 93b

94

95 95a, 95b

96 96a, 96b

97 97a, 97b

98 98a, 98b

99

100

101

102 102a, 102b

103

104 104a, 104b

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123 123a, 123b

124

125

126

127 127a, 127b, 127c, 127d

128 128a, 128b

129 129a, 129b, 129c, 129d

130 130a, 130b

131 131a, 131b

132

133 133a, 133b

134 134a, 134b

135 135a, 135b

136 136a, 136b

137 137a, 137b

138 138a, 138b

139 139a, 139b

140 140a, 140b

141 141a, 141b

142 142, 142b

143 143a, 143b

144 144a, 144b

145 145a, 145b

146 146a, 146b

147 147a, 147b

148 148a, 148b, 148a, 148d

149 149a, 149b

150 150a, 150b

151 151a, 151b

152 152a, 152b

153 153a, 153b

154 154a, 154b

155 155a, 155b, 155c, 155d

156 156a, 156b

157 157a, 157b

158 158a, 158b

159 159a, 159b

160 160a, 160b

161 161a, 161b, 161c, 161d

162 162a, 162b, 162c, 162d

163 163a, 163b, 163c, 163d

164 164a, 164b, 164c, 164d

165 165a, 165b

166 166a, 166b

167 167a, 167b

168 168a, 168b 168c, 168d

169 169a, 169b

170 170a, 170b

171 171a, 171b

172 172a, 172b

173 173a, 173b

174 174a, 174b

175 175a, 175b

176 176a, 176b, 176c, 176d

177 177a, 177b, 177c, 177d

178 178a, 178b

179 179a, 179b

180

181

182

183 183a, 183b

184

185

186

187

188

189

190

191

192 192a, 192b, 192c, 192d

193 193a, 193b

194 194a, 194b

195 195a, 195b

196 196a, 196b

197 197a, 197b

198 198a, 198b, 198c, 198d

199 199a, 199b

200

201

202

203

204

205

206

207

208

209

210

211 211a, 211b

212

213

214

215

216

217

218

219

220 220a, 220b

221 221a, 221b

222

223 223a, 223b

224

225 225a, 225b

226

227

228

229

230

231 231a, 231b

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253 253a, 253b

254 254a, 254b

255 255a, 255b

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272 272a, 272b

273

274 274a, 274b

275

276

277

278

279

280

281

282

283

284

285

286

287

288 288a, 288b

289 289a, 289b

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314 314a, 314b

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336 336a, 336b

337 337a, 337b

338 338a, 338b

339 339a, 339b

340 340a, 340b, 340c, 340d

341 341a, 341b, 341c, 341d

342 342a, 342b, 342c, 342d

TABLE 2 Representative Compounds of the Invention

  II-1 II-1a, II-1b

  II-2

  II-3

  II-4 II-4a, II-4b, II-4c, II-4d

  II-5 II-5a, II-5b, II-5c, II-5d

  II-6 II-6a, II-6b, II-6c, II-6d

  II-7 II-7a, II-7b, II-7c, II-7d

  II-8 II-8a, II-8b

  II-9 II-9a, II-9b

  II-10 II-10a, II-10b

  II-11 II-11a, II-11b

  II-12 II-12a, II-12b

  II-13 II-13a, II-13b

  II-14 II-14a, II-14b

  II-15 II-15a, II-15b

  II-16 II-16a, II-16b

  II-17 II-17a, II-17b, II-17c, II-17d

  II-18

  II-19 II-19a, II-19b

  II-20 II-20a, II-20b

  II-21 II-21a, II-21b

  II-22 II-22a, II-22b

  II-23 II23a, II-23b

  II-24 II-24a, II-24b

  II-25 II-25a, II-25b

  II-26 II-26a, II-26b

  II-27 II-27a, II-27b

  II-28 II-28a, II-28b

  II-29 II-29a, II-29b

  II-30 II-30a, II-30b

  II-31 II-31a, II-31b

  II-32 II-32a, II-32b

  II-33 II-33a, II-33b

  II-34 II-34a, II-34b

  II-35 II-35a, II-35b

  II-36 II-36a, II-36b

  II-37 II-37a, II-37b

  II-38 II-38a, II-38b

  II-39

  II-40

  II-41 II-41a, II-41b

  II-42 II-42a, II-42b

  II-43 II-43a, II-43b

  II-44 II-44a, II-44b

  II-45 II-45a, II-45b

  II-46 II-46a, II-46b

  II-47 II-47a, II-47b

  II-48 II-48a, II-48b

  II-49 II-49a, II-49b

  II-50 II-50a, II-50b

  II-51 II-51a, II-51b

  II-52 II-52a, II-52b

  II-53 II-53a, II-53b

  II-54 II-54a, II-54b

  II-55 II-55a, II-55b

  II-56 II-56a, II-56b

  II-57 II-57a, II-57b

  II-58 II-58a, II-58b

  II-59

  II-60 II-60a, II-60b

  II-61

  II-62 II-62a, II-62b

  II-63 II-63a, II-63b

  II-64 II-64a, II-64b

  II-65 II-65a, II-65b

  II-66 II-66a, II-66b

  II-67 II-67a, II-67b

  II-68 II-68a, II-68b

  II-69 II-69a, II-69b, II-69c, II-69d

  II-70

  II-71 II-71a, II-71b

  II-72 II-72a, II-72b, II-72c, II- 72d

  II-73 II-73a, II-73b, II-73c, II-73d

  II-74 II-74a, II-74b, II-74c, II-74d

  II-75 II-75a, II-75b

  II-76

  II-77

  II-78 II-78a, II-78b

  II-79 II-79a, II-79b, II-79c, II-79d

  II-80 II-80a, II-80b

  II-81 II-81a, II-81b

  II-82

  II-83 II-83a, II-83b, II-83c, II-83d

  II-84 II-84a, II-84b

  II-85 II-85a, II-85b, II-85c, II-85d

  II-86 II-86a, II-86b, II-86c, II-86d

  II-87 II-87a, II-87b

  II-88 II-88a, II-88b

  II-89 II-89a, II-89b

  II-90 II-90a, II-90b

  II-91 II-91a, II-91b

  II-92 II-92a, II-92b

  II-93 II-93a, II-93b

  II-94 II-94a, II-94b

  II-95 II-95a, II-95b, II-95c, II-95d

  II-96

  II-97 II-97a, II-97b

  II-98 II-98a, II-98b, II-98c, II-98d

  II-99 II-99a, II-99b

  II-100 II-100a, II-100b

  II-101

  II-102 II-102a, II-102b

  II-103

  II-104 II-104a, II-104b

  II-105 II-105a, II-105b

  II-106 II-106a, II-106b

  II-107 II-107a, II-107b, II- 107c, II-107d

  II-108 II-108a, II-108b

  II-109 II-109a, II-109b

  II-110

  II-111 II-111a, II-111b

  II-112 II-112a, II-112b, II- 112c, II-112d

  II-113 II-113a, II-113b, II- 113c, II-113d

  II-114 II-114a, II-114b

  II-115 II-115a, II-115b, II- 115c, II-115d

  II-116 II-116a, II-116b

  II-117 II-117a, II-117b

  II-118 II-118a, II-118b

  II-119

  II-120 II-120a, II-120b, II- 120c, II-120d

  II-121 II-121a, II-121b, II- 121c, II-121d

  II-122 II-122a, II-122b, II- 122c, II-122d

  II-123 II-123a, II-123b

  II-124 II-124a, II-124b

  II-125 II-125a, II-125b, II- 125c, II-125d

  II-126 II-126a, II-126b

  II-127 II-127a, II-127b, II- 127c, II-127d

  II-128 II-128a, II-128b, II- 128c, II-128d

  II-129 II-129a, II-129b

  II-130 II-130a, II-130b, II- 130c, II-130d

  II-131 II-131a, II-131b, II- 131c, II-131d

  II-132 II-132a, II-132b, II- 132c, II-132d

  II-133

  II-134 II-134a, II-134b

  II-135 II-135a, II-135b

  II-136 II-136a, II-136b

  II-137 II-137a, II-137b

  II-138 II-138a, II-138b, II- 138c, II-138d

  II-139 II-139a, II-139b, II- 139c, II-139d

  II-140 II-140a, II-140b, II- 140c, II-140d

  II-141 II-141a, II-141b

  II-142 II-142a, II-142b

  II-143 II-143a, II-143b

  II-144

  II-145 II-145a, II-145b

  II-146 II-146a, II-146b, II- 146c, II-146d

  II-147 II-147a, II-147b, II- 147c, II-147d

  II-148 II-148a, II-148b

  II-149 II-149a, II-149b, II- 149c, II-149d

  II-150 II-150a, II-150b, II- 150c, II-150d

  II-151 II-151a, II-151b, II- 151c, II-151d

  II-152 II-152a, II-152b, II- 152c, II-152d

  II-153 II-153a, II-153b

  II-154 II-154a, II-154b

  II-155 II-155a, II-155b

  II-156 II-156a, II-156b

  II-157 II-157a, II-157b

  II-158 II-158a, II-158b

  II-159 II-159a, II-159b

  II-160 II-160a, II-160b

  II-161 II-161a, II-161b, II- 161c, II-161d

  II-162 II-162a, II-162b

  II-163 II-163a, II-163b

  II-164 II-164a, II-164b, II- 164c, II-164d

  II-165 II-165a, II-165b, II- 165c, II-165d

  II-166 II-166a, II-166b

  II-167 II-167a, II-167b

  II-168 II-168a, II-168b

  II-169 II-169a, II-169b

  II-170 II-170a, II-170b

  II-171 II-171a, II-171b

  II-172 II-172a, II-172b

  II-173 II-173a, II-173b

  II-174 II-174a, II-174b

  II-175 II-175a, II-175b

  II-176 II-176a, II-176b

  II-177 II-177a, II-177b

  II-178 II-178a, II-178b

  II-179 II-179a, II-179b

  II-180 II-180a, II-180b

  II-181 II-181a, II-181b

  II-182 II-182a, II-182b

  II-183 II-183a, II-183b

  II-184 II-184a, II-184b

  II-185 II-185a, II-185b, II- 185c, II-185d

  II-186

  II-187 II-187a, II-187b

  II-188 II-188a, II-188b

  II-189 II-189a, II-189b

  II-190 II-190a, II-190b

  II-191 II-191a, II-191b

  II-192 II-192a, II-192b

  II-193 II-193a, II-193b

  II-194 II-194a, II-194b

  II-195 II-195a, II-195b

  II-196 II-196a, II-196b

  II-197 II-197a, II-197b

  II-198 II-198a, II-198b

  II-199 II-199a, II-199b

  II-200 II-200a, II-200b

  II-201 II-201a, II-201b

  II-202 II-202a, II-202b

  II-203 II-203a, II-203b

  II-204 II-204a, II-204b

  II-205 II-205a, II-205b

  II-206 II-206a, II-206b

  II-207 II-207a, II-207b

  II-208 II-208a, II-208b

  II-209

  II-210 II-210a, II-210b

  II-211 II-211a, II-211b

  II-212 II-212a, II-212b

  II-213 II-213a, II-213b

  II-214 II-214a, II-214b

  II-215

  II-216 II-216a, II-216b

  II-217 II-217a, II-217b

  II-218 II-218a, II-218b

  II-219 II-219a, II-219b, II- 219c, II-219d

  II-220 II-220a, II-220b

  II-221 II-221a, II-221b

  II-222 II-222a, II-222b

  II-223 II-223a, II-223b

  II-224 II-224a, II-224b

  II-225 II-225a, II-225b

  II-226 II-226a, II-226b

  II-227 II-227a, II-227b, II- 227c, II-227d

  II-228 II-228a, II-228b

  II-229 II-229a, II-229b

  II-230 II-230a, II-230b

  II-231 II-231a, II-231b

  II-232 II-232a, II-232b

  II-233

  II-234 II-234a, II-234b

  II-235 II-235a, II-235b

  II-236 II-236a, II-236b

  II-237

  II-238 II-238a, II-238b

  II-239 II-239a, II-239b

  II-240

  II-241 II-241a, II-241b

  II-242 II-242a, II-242b

  II-243 II-243a, II-243b

  II-244 II-244a, II-244b

  II-245 II-245a, II-245b

  II-246

  II-247

  II-248

  II-249

  II-250

  II-251

  II-252

  II-253

  II-254

  II-255 II-255a, II-255b

  II-256 II-256a, II-256b

  II-257 II-257a, II-257b

  II-258 II-258a, II-258b

  II-259 II-259a, II-259b

  II-260 II-260a, II-260b

  II-261 II-261a, II-261b, II- 261c, II-261d

  II-262 II-262a, II-262b

  II-263 II-263a, II-263b

  II-264 II-264a, II-264b

  II-265 II-265a, II-265b

  II-266 II-266a, II-266b, II- 266c, II-266d

  II-267 II-267a, II-267b

  II-268 II-268a, II-268b

  II-269 II-269a, II-269b

  II-270 II-270a, II-270b

  II-271 II-271a, II-271b, II- 271c, II-271d

  II-272

  II-273

  II-274 II-274a, II-274b

  II-275 II-275a, II-275b, II- 275c, II-275d

  II-276 II-276a, II-276b, II- 276c, II-276d

  II-277 II-277a, II-277b

  II-278 II-278a, II-278b

  II-279 II-279a, II-279b, II- 279c, II-279d

  II-280 II-280a, II-280b, II- 280c, II-280d

  II-281 II-281a, II-281b, II- 281c, II-281d

  II-282 II-282a, II-282b, II- 282c, II-282d, II-282e, II-282f, II-282g,II-282h

  II-283 II-283a, II-283b, II- 283c, II-283d

  II-284 II-284a, II-284b, II- 284c, II-284d

  II-285 II-285a, II-285b, II- 285c, II-285d

  II-286

  II-287 II-287a, II-287b, II- 287c, II-287d

  II-288 II-288a, II-288b, II 288c, II-288d

  II-289 II-289a, II-289b

  II-290 II-290a, II-290b

  II-291 II-291a, II-291b, II- 291c, II-291d

  II-292 II-292a, II-292b

  II-293 II-293a, II-293b, II- 293c, II-293d

  II-294 II-294a, II-294b, II- 294c, II-294d

  II-295 II-295a, II-295b

  II-296 II-296a, II-296b

  II-297 II-297a, II-297b

  II-298 II-298a, II-298b

  II-299

TABLE 3 Representative Compounds of the Invention.

TABLE 4 Representative Compounds of the Invention

IV-1

IV-2

IV-3

IV-4

IV-5

IV-6

IV-7

IV-8

IV-9

IV-10

IV-11

IV-12

IV-13

IV-14

IV-15

IV-16

IV-17

IV-18

IV-19

IV-20

IV-21

IV-22

IV-23

IV-24

IV-25

IV-26

IV-27

IV-28

IV-29

IV-30

IV-31

IV-32

IV-33

IV-34

IV-35

IV-36

IV-37

IV-38

IV-39

IV-40

IV-41

IV-42

IV-43

IV-44

IV-45

IV-46

IV-47

IV-48

IV-49

IV-50

IV-51

IV-52

IV-53

IV-54

IV-55

IV-56

IV-57

IV-58

IV-59

IV-60

IV-61

IV-62

IV-63

IV-64

IV-65

IV-66

IV-67

IV-68

IV-69

IV-70

IV-71

IV-72

IV-73

IV-74

IV-75

IV-76

IV-77

IV-78

IV-79

IV-80

IV-81

IV-82

IV-83

IV-84

IV-85

IV-86

IV-87

IV-88

IV-89

IV-90

IV-91

IV-92

IV-93

IV-94

IV-95

IV-96

IV-97

IV-98

IV-99

IV-100

IV-101

IV-102

IV-103

IV-104

IV-105

IV-106

IV-107

IV-108

IV109

IV-110

IV-111

IV-112

IV-113

IV-114

IV-115

IV-116

IV-117

IV-118

IV-119

IV-120

IV-121

IV-122

IV-123

IV-124

IV-125

IV-126

IV-127

IV-128

IV-129

IV-130

IV-131

IV-132

IV-133

IV-134

IV-135

IV-136

IV-137

IV-138

IV-139

IV-140

IV-141

IV-142

IV-143

IV-144

IV-145

IV-146

IV-147

IV-148

IV-149

IV-150

IV-151

IV-152

IV-153

IV-154

IV-155

IV-156

IV-157

IV-158

IV-159

IV-160

IV-161

IV-152

IV-163

IV-164

IV-165

IV-166

IV-167

IV-168

IV-169

IV-170

IV-171

IV-172

IV-173

IV-174

IV-175

IV-176

IV-177

IV-178

IV-179

IV-180

IV-181

IV-182

IV-183

IV-184

IV-185

IV-186

IV-187

IV-188

IV-189

IV-190

IV-191

IV-192

IV-193

IV-194

IV-195

IV-196

IV-197

IV-198

IV-199

IV-200

IV-201

IV-202

IV-203

IV-204

IV-205

IV-206

IV-207

IV-208

IV-209

IV-210

IV-211

IV-212

IV-213

IV-214

IV-215

IV-216

IV-217

IV-218

IV-219

IV-220

IV-221

IV-222

IV-223

IV-224

IV-225

IV-226

IV-227

IV-228

IV-229

IV-230

IV-231

IV-232

IV-233

IV-234

IV-235

IV-236

IV-237

IV-238

IV-239

IV-240

IV-241

IV-242

IV-243

IV-244

TABLE 5 Representative Compounds of the Invention

General Synthetic Methods

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process descriptions, the symbols whenused in the formulae depicted are to be understood to represent thosegroups described above in relation to the formulae herein.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g., a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

General Protocol for Chiral Preparative HPLC Separation of RacemicCompounds

For chiral separations, samples were dissolved in MeOH and EtOHaccording to the solubility of sample and filtered through 0.2μ PTFEfilters. The columns used were CHIRALPAK-AD; 20*250 mm, 10μ andCHIRALCEL-ODH; 20*250 mm, 5μ. A flow rate of 12 mL/min-17 mL/min wasused according to the resolution. Alkanes such as n-Pentane, Hexane andHeptane (40%-95%) and alcohols such as EtOH, Isopropyl alcohol andt-Butanol (5%-60%) were used as mobile phase. In some cases alcoholcombinations i.e. (EtOH+MeOH), (EtOH+IPA), (IPA+MeOH), (t-Butanol+MeOH),(t-Butanol+EtOH) were used instead of a single alcohol. Diethyl amine(up to 0.3%) was used as modifier in the mobile phase.

Example H1 General Method for the Chiral HPLC Separation andCharacterization of Compounds that were Synthesized Initially as aMixture of Enantiomers

Crude or in some cases partially purified (normal or reverse phase HPLC)mixtures of enantiomers were analyzed by analytical chiral HPLC methods.Once adequate separation was achieved, larger quantities of the mixtureswere separated using preparative scale columns as shown below forCompound Nos. 138a and 138b. Separation was followed by removal ofsolvents on a rotary evaporator to accomplish the isolation of theindividual single enantiomers. In some cases where appropriate, afterremoval of solvent, the samples were lyophilized. After isolation, eachindividual enantiomer was further analyzed by analytical (reverse phaseand chiral) HPLC, LCMS and NMR. When final products were converted tosalts, final characterization of the compounds was carried out afterconversion to the salt for each enantiomer.

Analytical Chiral HPLC of Compound Nos. 138a and 138b.

Column: Chiralcel OD-H; Column ID: 4.6*250 mm, 5μ. Mobile Phase:Hexane:(EtOH:MeOH 80:20)-93:7. Flow rate: 1 mL/min. Retention Time:Compound No. 138a-9.939 min. Compound No. 138b-13.660 min.

Chiral Preparative Data of Compound Nos. 138a and 138b.

Column: Chiralcel OD-H. Column ID: 20*250 mm, 5μ. Mobile Phase: Hexane:(EtOH:MeOH 80:20)-95:5. Flow rate: 15 mL/min. Solubility: 30 mg/mL inMeOH.

Example H2 General Method for the Chiral HPLC Separation andCharacterization of Compounds that were Synthesized Initially as aMixture of Diastereomers

Crude or in some cases partially purified (normal or reverse phase HPLC)mixtures of diastereomers were analyzed by analytical chiral HPLCmethods. Once adequate separation was achieved, larger quantities of themixtures were separated using preparative scale columns as shown belowfor Compound Nos. II-149a-d. Separation was followed by removal ofsolvents on a rotary evaporator to accomplish the isolation of theindividual single diastereomers. In some cases where appropriate, afterremoval of solvent, the samples were lyophilized. Once each individualdiastereomer was isolated they were further analyzed by analytical(reverse phase and chiral) HPLC, LCMS and NMR. When final products wereconverted to salts, final characterization of the compounds was carriedout after conversion to the salt for each diastereomer.

Analytical Chiral HPLC Data of Compound Nos. II-149a-d.

Column: Chiral Pak AD-H. Column ID: 4.6*250 mm, 5μ. Mobile Phase: Hexane(0.2% diethylamine):Isopropanol—93:7. Flow rate: 1 mL/min. RetentionTime: Compound No. II-149a—15.470 min. Compound No. II-149b—19.808 min.Compound No. II-149c—33.280 min. Compound No. II-149d—39.585 min.

Chiral Preparative Data of Compound Nos. II-149a-d.

Column: Chiral PAK-AD-H. Column ID: 20*250 mm, 5μ. Mobile Phase: Hexane(0.2% diethylamine):Isopropanol—93:7. Flow rate: 15 mL/min. Solubility:40 mg/mL in MeOH.

The following abbreviations are used herein: thin layer chromatography(TLC); hour (h); minute (min); second (sec); ethanol (EtOH);dimethylsulfoxide (DMSO); N,N-dimethylformamide (DMF); trifluoroaceticacid (TFA); tetrahydrofuran (THF); Normal (N); aqueous (aq.); methanol(MeOH); dichloromethane (DCM); ethyl acetate (EtOAc); Retention factor(Rf); room temperature (RT).

Compounds detailed herein may be prepared by those of skill in the artby referral to General Methods and Examples described in published PCTapplications WO2009/055828 (see e.g., General Methods 1-24 and Examples1-325), WO2010/127177 (General Methods 1-3 and Examples 1-58),WO2009/120720 (General Methods 1-15C and Examples 1-134), WO2009/120717(General Methods 1-17 and Examples 1-134), WO2010/051501 (GeneralMethods 1-10 and Examples 1-450) and WO2010/051503 (General Methods 1-15and Examples 1-111), WO2011/019417 (General Methods 1-9 and Examples1-10), WO2011/038164 (General Methods 1-19), WO2011/038162 (GeneralMethods 1-21 and Examples 1-6), WO2011/038163 (General Methods 1-19 andExamples 1-49) and WO2011/038161 (General Methods 1-15B and Examples1-22). The PCT publications described above are incorporated herein byreference in their entireties. Particular examples of each of theGeneral Methods and Examples are provided in the Examples below.

General Method 1

In certain examples of formula (I) provided herein, and as similarlydescribed in the publications presented above, alcohols of the type Ccan be prepared by treating appropriately functionalized carboline Awith functionalized epoxide B, in the presence of a base. A selection ofbases effective for this reaction will be apparent to those skilled inthe art, such as for example, sodium hydride, sodium tert-butoxide,potassium tert-butoxide, lithium tert-butoxide, lithiumdiisopropylamide, lithium hexamethyldisilazide, sodium ethoxide, sodiummethoxide, and the like. In some instances, one or more of the bases maybe used interchangeably; for example, other bases such as sodiumtert-butoxide, potassium tert-butoxide, lithium tert-butoxide, lithiumdiisopropylamide, lithium hexamethyldisilazide, sodium ethoxide orsodium methoxide may be substituted where sodium hydride is specificallydescribed. It is understood that modifications to the specific materialsshown are intended, e.g., where Compound B can be a heteroaryl groupsuch as pyridyl, and Compound A can comprise structures such aspyrido[3,4-b]indoles, azepino[4,5-b]indoles, andindolizino[7,8-b]indoles, and the like.

The following Examples are provided to illustrate but not to limit theinvention.

All references disclosed herein are incorporated herein by reference intheir entireties.

EXAMPLES Example 1 Preparation of Compound Nos. 1, 1a and 1b

Sodium hydride (1-3 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.)in DMF and heated to 120° C. for 1 h with stirring. The reaction mixturewas cooled to 0° C. and 4-(2-methyloxiran-2-yl)pyridine (2-7.5 equiv.)was added dropwise over 5 min. The temperature was raised to 120° C. andstirred for 2 h. The reaction mixture was cooled to RT and partitionedbetween EtOAc and water. The organic layer was separated and the aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith water and followed by brine, dried over anhydrous sodium sulfateand concentrated under vacuum to provide the crude product. The productwas purified by flash column chromatography over silica gel (230-400mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to15% MeOH/EtOAc to yield the free base. The pure compound was convertedto its oxalate salt. The analytical sample was prepared by dissolvingfree base in THF and treatment with 1 equiv. of oxalic acid dihydrate.¹H NMR (CDCl₃, oxalate salt) δ (ppm): 8.42 (d, 2H), 7.35-7.20 (m, 3H),7.00-6.90 (m, 2H), 4.10 (q, 2H), 3.50 (q, 2H), 2.95-2.68 (m, 4H), 2.42(s, 3H), 1.55 (s, 3H). Separation by chiral HPLC provides enantiomers 1aand 1b.

Example 2 Preparation of Compound Nos. 2, 2a and 2b

Sodium hydride (1-3 equiv.) was added to a solution of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (1.0 equiv.) inDMF, and heated to 120° C. for 1 h with stirring. The reaction mixturewas cooled to 0° C. and 4-(2-methyloxiran-2-yl)pyridine (2-7.5 equiv.)was added dropwise over 5 min. The temperature was raised to 120° C. andstirred for 2 h. The reaction mixture was cooled to RT and partitionedbetween EtOAc and water. The organic layer was separated and the aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith water and followed by brine, dried over anhydrous sodium sulfateand concentrated under vacuum to provide the crude product. The productwas purified by flash column chromatography over silica gel (230-400mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to15% MeOH/EtOAc to yield the free base. The pure compound was convertedto its oxalate salt. The analytical sample was prepared by dissolvingfree base in THF and treatment with 1 equiv. of oxalic acid dihydrate.¹H NMR (CD₃OD, oxalate salt) δ (ppm): 8.38 (d, 2H), 7.50 (d, 2H), 7.15(s, 1H), 7.06 (d, 1H), 6.86 (d, 1H), 4.45 (m, 2H), 4.31 (m, 1H), 4.22(m, 1H), 3.61 (m, 2H), 3.19 (m, 1H), 3.06 (s, 3H), 2.78 (m, 2H), 2.35(s, 3H), 1.60 (s, 3H). Separation by chiral HPLC provides enantiomers 2aand 2b.

Example 3 Preparation of Compound Nos. 3, 3a and 3b

Sodium hydride (2.4 g, 100 mmol) was washed with hexane and dried undervacuum. To this was added DMF (15 mL) and cooled to 0° C. Then to thiswas added 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (4 g,20 mmol) and the mixture stirred at 0° C. for 30 min. Then4-oxiranyl-pyridine (2.90 g, 23.96 mmol) was dissolved in 5 mL DMF andadded dropwise to the mixture, which was then left stirred at RTovernight. The reaction was monitored by TLC. The reaction mixture waspoured into ice water and extracted with EtOAc (3×). The combinedorganic layer was washed with water, dried over anhydrous sodium sulfateand concentrated. The resultant solid material was washed with hexaneand crystallized from EtOH and ether. ¹H NMR (DMSO-d6, HCl salt) δ(ppm): 8.70 (d, 2H), 7.70 (d, 2H), 7.38 (m, 1H), 7.20 (s, 1H), 6.90 (d,1H), 5.05 (m, 1H), 4.58 (m, 1H), 4.30 (m, 1H), 4.20 (m, 2H), 3.70 (m,2H), 3.20 (m, 4H), 2.90 (s, 1H), 2.38 (s, 3H). Separation by chiral HPLCprovided enantiomers 3a and 3b. Optical rotations: Compound No. 3a;(−)31.32 (c 1, Chloroform, 94.1% HPLC purity); Compound No. 3b, (+)28.24(c 1, Chloroform, 98.05% HPLC purity).

Example 4 Preparation of Compound Nos. 4, 4a, and 4b

Sodium hydride (2.72 g, 113.33 mmol) was washed with hexane and driedunder vacuum. To this was added DMF (15 mL) and the mixture cooled to 0°C. 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (5 g,22.72 mmol) was added and the mixture stirred at 0° C. for min, followedby 4-oxiranyl-pyridine (3.3 g, 27.27 mmol) dissolved in 5 mL DMF addeddropwise. The reaction mixture was stirred at RT overnight. The reactionwas monitored by TLC. The reaction mixture was poured into ice water andthe product extracted into EtOAc (3×). The combined organic layers werewashed with water, dried over anhydrous sodium sulfate and concentrated.The resultant solid material was washed with hexane and crystallizedfrom EtOH and ether. ¹H NMR (CD₃OD, HCl salt) δ (ppm): 8.80 (d, 2H),8.18 (d, 2H), 7.50 (s, 1H), 7.30 (m, 1H), 7.10 (d, 1H), 5.30 (m, 1H),4.70 (m, 1H), 4.50 (m, 1H), 4.40 (m, 2H), 3.90 (m, 1H), 3.60 (m, 2H),3.40 (m, 2H), 3.10 (s, 3H). Separation by chiral HPLC providedenantiomers 4a and 4b. Optical rotations: Compound No. 4a, (+)47.31 (c0.58, Chloroform, 96.26% HPLC purity); Compound No. 4b, (−)43.75 (c0.55, Chloroform, 98.59% HPLC purity).

Example 5 Preparation of Compound Nos. 5, 5a and 5b

To a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(290 mg, 1.4 mmol) in DMF (6 mL) was added sodium hydride (38 mg, 1.6mmol) and the solution was stirred at 120° C. for 1 h. The reactionmixture was cooled to 0° C. and 3-(2-methyloxiran-2-yl)pyridine (400 mg,2.96 mmol) was added dropwise over a period of 5 min. The reactionmixture was stirred at 120° C. for 2 h, quenched with ice-water (15 mL)and extracted with EtOAc (60 mL). The organic layer was washed withwater, brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by flash columnchromatography (5-15% MeOH/EtOAc) to yield1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-yl)propan-2-ol.Separation by chiral HPLC provided enantiomers 5a and 5b. ¹H NMR (CDCl₃,freebase) δ (ppm): 8.79 (s, 1H), 8.42 (d, 1H), 7.56 (d, 1H), 7.04 (s,1H), 6.9 (m, 2H), 6.8 (d, 1H), 4.17 (dd, 2H), 3.42 (s, 2H), 2.8 (t, 2H),2.62 (t, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 1.61 (s, 3H). Opticalrotations: Compound No. 5a, (−)39.27 (c 0.43, Chloroform, 99.69% HPLCpurity); Compound No. 5b, (+)58.97 (c 0.58, Chloroform, 99.49% HPLCpurity).

Example 6 Preparation of Compound Nos. 6, 6a and 6b

To a solution of2-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(1.0 g, 3.937 mmol) in DMF (10 mL) was added sodium hydride (472 mg,11.81 mmol) in portions at RT. After stirring at RT for 15 min, thesuspension was allowed to cool to 0° C. and 4-(oxiran-2-yl)pyridine (762mg, 6.299 mmol) was added dropwise into the reaction mixture, which wasstirred at RT overnight. The reaction mixture was poured into ice-cooledwater and extracted with EtOAc (3×50 mL). The organic layer was washedwith water (2×50 mL), dried over anhydrous sodium sulfate andconcentrated. The solid obtained was re-crystallized in DCM-diethylether to yield2-(2-methyl-8-(trifluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.59 (d, 2H), 7.4 (s, 1H), 7.39 (d,1H), 7.3 (d, 1H), 7.19 (d, 2H), 4.68 (m, 1H), 4.1 (m, 2H), 3.4 (dd, 2H),2.82 (m, 1H), 2.74 (bs, 2H), 2.6 (m, 1H), 2.4 (s, 3H). Separation bychiral HPLC provides enantiomers 6a and 6b.

Example 7 Preparation of Compound Nos. 7, 7a and 7b

Chloro carboline (500 mg, 2.27 mmol) was taken in DMF. NaH (180 mg, 4.5mmol) was added at RT and stirred for 10-15 min. Neat epoxide (450 mg,3.7 mmol) was added dropwise at RT. The reaction was stirred at RT for 4h and the reaction was monitored by LCMS. After completion, the reactionmixture was poured on ice water and extracted with EtOAc, dried andconcentrated. The residue was purified by HPLC. 465 mg of product as awhite solid (TFA salt). TLC: 5% MeOH-DCM, Rf 0.1 was observed. ¹H NMR(CD₃OD, TFA salt) δ (ppm): 8.80 (s, 2H), 8.40 (s, 1H), 7.9 (t, 1H), 7.40(s, 1H), 7.20 (d, 1H), 7.0 (d, 1H), 5.25 (bs, 1H), 4.7 (d, 1H), 4.4 (m,2H), 4.3 (d, 1H), 3.9 (bs, 1H), 3.5 (bs, 1H), 3.3 (m, 2H), 3.10 (s, 3H).Separation by chiral HPLC provided enantiomers 7a and 7b. Opticalrotations: Compound 7a, (−)21.05 (c 0.52, Chloroform, 89.7% HPLCpurity); Compound 7b, (+)6.85 (c 0.69, Chloroform, 95.74% HPLC purity).

Example 8 Preparation of Compound Nos. 8, 8a and 8b

To a solution of 2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(1.0 g, 5.00 mmol) in DMF (20 mL) was added sodium hydride (600 mg, 15mmol), the suspension stirred at RT for 10 min. A solution of4-(oxiran-2-yl)pyridine (1.21 g, 10 mmol) in DMF (5 mL) was added slowlyinto the reaction mixture which was stirred at RT overnight. Theprogress of reaction was monitored by TLC and LCMS. The reaction masswas poured into ice cold water (200 mL) slowly and extracted with EtOAc(3×200 mL). The organic layer was washed with water (4×300 mL), driedover anhydrous sodium sulfate and concentrated. The residue obtained waswashed with hexane (2×15 mL) and triturated with diethyl ether (50 mL)to yield the desired product. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.62 (d,2H), 7.31 (d, 2H), 7.28 (s, 1H), 7.21 (d, 1H), 7.02 (d, 1H), 5.05 (m,1H), 4.14 (dd, 1H), 4.078 (dd, 1H), 3.74 (d, 1H), 3.37 (d, 1H), 2.83 (m,3H), 2.72 (m, 1H), 2.51 (s, 3H), 2.46 (s, 3H). Separation by chiral HPLCprovided enantiomers 8a and 8b.

Example 9 Preparation of Compound Nos. 9, 9a and 9b

2-(2-Allyl-8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-3-yl-ethanol(1.0 g, 2.8 mmol) was dissolved in DCM and the solution was purged withnitrogen for 5 min. 1,3-Dimethylbarbituric acid (1.34 g, 8.6 mmol) andPd(PPh₃)₄ (66.5 mg, 0.056 mmol) were added and the reaction mixture wasstirred at RT for 3 h. The reaction mixture was concentrated underreduced pressure, and the residue was basified with saturated aqueouspotassium carbonate, and extracted with EtOAc (3×50 mL). The combinedorganic layer was washed with saturated aqueous potassium carbonate(6×20 mL), dried over anhydrous sodium sulfate and concentrated. Thecrude product was purified by reverse phase chromatography to obtain 50mg of2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-3-yl-ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.47 (s, 1H), 8.41 (d, 1H), 7.59 (d,1H), 7.19 (m, 3H), 7.10 (s, 1H), 7.00 (d, 1H), 5.0 (t, 1H), 4.10 q (d,2H), 3.92 q (d, 2H), 3.10 (m, 2H), 2.90 (m, 2H), 2.47 (m, 1H), 2.42 (s,3H). This racemate was separated by chiral semi-preparative HPLC toobtain enantiomers 9a and 9b.

Example 10 Preparation of Compound Nos. 10, 10a and 10b

2-(2-Allyl-8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol(4.0 g, 10.87 mmol) was dissolved in DCM (350 mL) and nitrogen waspurged for 10 min into the reaction mixture. 1,3-Dimethyl barbituricacid (5.08 g, 32.62 mmol) and Pd(PPh₃)₄ (251 mg, 0.217 mmol) was addedand stirred for 2 h at RT. After consumption of starting material, thereaction mixture was diluted with saturated potassium carbonate (200 mL)and extracted with DCM (2×100 mL). The combined organic layer was driedover anhydrous sodium sulfate and concentrated, and the crude mixturecrystallized in MeOH (5 mL) and ether (50 mL) to obtain 2.2 g of2-(8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.58 (d, 2H), 7.37 (s, 1H), 7.25 (d,2H), 7.23 (d, 1H), 7.13 (d, 1H), 5.0 (t, 1H), 4.15 (d, 2H), 3.99 (s,2H), 3.19 (m, 2H), 2.81 (m, 1H), 2.53 (m, 1H). Separation by chiral HPLCprovided enantiomers 10a and 10b. Optical rotations: Compound No. 10a,(−)34.60 (c 0.55, Chloroform, 99.16% HPLC purity); Compound No. 10b,(+)31.78 (c 0.53, Chloroform, 92.71% HPLC purity).

Example 11 Preparation of Compound Nos. 11, 11a and 11b

3-[8-Chloro-5-(2-hydroxy-2-pyridin-4-yl-ethyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-propionicacid methyl ester (200 mg, 0.484 mmol) was dissolved in dry THF (5 mL),and cooled to −78° C. Methyl magnesium chloride (0.2 mL, 1.93 mmol) wasadded dropwise and stirred for 15 min and allowed to RT and stirred for2 h. After consumption of starting material, 2 mL MeOH was added intothe reaction, which was then concentrated, and the residue diluted withwater (20 mL) and extracted with EtOAc (3×30 mL). The combined organiclayer was dried over anhydrous sodium sulfate and concentrated, and thecrude product purified by reverse phase chromatography to obtain 50 mgof4-[8-chloro-5-(2-hydroxy-2-pyridin-4-yl-ethyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-2-methyl-butan-2-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.48 (d, 2H), 7.35 (s, 1H), 7.18 (d,2H), 7.16 (d, 1H), 7.10 (d, 1H), 4.90 (t, 1H), 4.05 (m, 2H), 3.68 (m,2H), 2.87 (m, 3H), 2.79 (m, 2H), 2.49 (m, 1H), 1.72 (t, 2H), 1.24 (s,6H). Separation by chiral HPLC provided enantiomers 11a and 1b. Opticalrotations: Compound No. 11a, (−)25.66 (c 0.56, Chloroform, 96.42% HPLCpurity); Compound No. 1b, (+)24.07 (c 0.56, Chloroform, 98.39% HPLCpurity).

Example 12 Preparation of Compound Nos. 12, 12a and 12b

1-(6-Allyl-3-chloro-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-2-pyridin-4-yl-propan-2-ol(260 mg, 0.680 mmol) was dissolved in DCM (7 mL) and N₂ was purged intothe reaction mixture. 1,3-Dimethyl barbituric acid (318 mg, 2.04 mmol)and Pd(PPh₃)₄ (15 mg, 0.013 mmol) was added and the mixture stirred for45 min at RT. After consumption of starting material, the reactionmixture was diluted with saturated potassium carbonate and extractedwith DCM (3×50 mL). The combined organic layer was dried over anhydroussodium sulfate and concentrated, and the crude product was purified byreverse phase chromatography to obtain 100 mg of1-(3-chloro-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-2-pyridin-4-yl-propan-2-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.51 (d, 2H), 8.14 (s, 1H), 7.67 (s,1H), 7.33 (d, 2H), 4.39 (d, 1H), 4.36 (d, 1H), 3.93 q (d, 2H), 3.16 (m,2H), 2.62 (m, 1H), 2.40 (m, 1H), 1.57 (s, 3H). Separation by chiral HPLCprovided enantiomers 12a and 12b. Optical rotations: Compound No. 12a,(+)121.78 (c 0.53, Chloroform, 97.32% HPLC purity); Compound No. 12b,(−)118.34 (c 0.54, Chloroform, 99.01% HPLC purity).

Example 13 Preparation of Compound Nos. 13, 13a and 13b

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg, 1.40mmol) was taken into DMF (6 mL). To a solution of sodium hydride (50%)(100 mg, 4.22 mmol) was added in portions at RT and stirred at RT for 10min. A solution of 4-(oxiran-2-yl)pyridine (254 mg, 2.11 mmol) in DMF (1mL) was added dropwise for 10 min. and stirred for 14 h at RT. Thereaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice water, extracted in ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure product2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanolas the TFA salt (250 mg). Separation by chiral HPLC provided enantiomers13a and 13b. Optical rotations: Compound No. 13a, (−)5.03 (c 0.56,Chloroform, 99.17% HPLC purity); Compound No. 13b, (+)5.70 (c 0.56,Chloroform, 99.35% HPLC purity).

Example 14 Preparation of Compound Nos. 14, 14a and 14b

2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (1 g, 5 mmol) wasdissolved in 15 mL DMF and stirred for 10 min at 0° C. Sodium hydride(600 mg, 15 mmol) was added portionwise at RT and stirred for 10 min.3-(2-Methyl-oxiranyl)-pyridine (1.01 g, 7.5 mmol) was added dropwise atthe same temperature and the mixture stirred for 12 h at RT. Thereaction was monitored by TLC & LCMS. After consumption of startingmaterial, the reaction mixture was quenched with ice water and extractedwith EtOAc (3×100 mL). The combined organic layer was washed with water(4×100 mL). The organic layer was dried over anhydrous sodium sulfateand concentrated and the residue was crystallized in EtOH and ether toobtain 375 mg of1-(2,6-dimethyl-1,2,3,4-tetrahydro-3-carbolin-9-yl)-2-pyridin-3-yl-propan-2-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.76 (d, 1H), 8.55 (dd, 1H), 7.703 (d,1H), 7.24 (s, 1H), 7.23 (dd, 1H), 7.15 (d, 1H), 6.95 (d, 1H), 4.13 (d,1H), 4.08 (d, 1H), 3.38 (dd, 2H), 2.79 (q, 2H), 2.74 (q, 2H), 2.46 (s,3H), 2.43 (s, 3H), 1.64 (s, 3H). Separation by chiral HPLC providedenantiomers 14a and 14b. Optical rotations: Compound No. 14a, (+)31.28(c 0.58, Chloroform, 96.04% HPLC purity); Compound No. 14b, (−)27.23 (c0.57, Chloroform, 96.09% HPLC purity).

Example 15 Preparation of Compound Nos. 15, 15a and 15b

9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (300 mg,1.27 mmol) was taken into DMF (6 mL). Sodium hydride (50%) (92 mg, 3.83mmol) was added in portions at RT and the mixture was stirred at RT for10 min. A solution of 4-(oxiran-2-yl)pyridine (232 mg, 1.9 mmol) in DMF(1 mL) was added dropwise for 10 min. and stirred for 14 h at RT. Thereaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice water, extracted in ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude product was purified by reverse phase chromatographyto get pure product2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanolas the TFA salt (230 mg). ¹HNMR (DMSO-d6, TFA salt) δ (ppm): 8.65 (m,2H), 7.80-7.45 (m, 3H), 7.40 (m, 1H), 7.0 (m, 1H), 6.0 (m, 1H), 4.95 (m,1H), 4.40 (m, 2H), 3.40 (m, 3H), 3.20 (m, 4H), 2.92 (s, 3H). Separationby chiral HPLC provided enantiomers 15a and 15b.

Example 16 Preparation of Compound Nos. 16, 16a and 16b

2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (500 mg, 2.5 mmol) wasdissolved in mL DMF and stirred for 10 min at RT. Sodium hydride (180mg, 7.5 mmol) was added portionwise at RT and the mixture stirred for 10min. 2-(2-Methyl-oxiranyl)-pyridine (472 mg, 3.5 mmol) was addeddropwise at the same temperature and stirred for 12 h at RT. Thereaction was monitored by TLC & LCMS. After consumption of startingmaterial, the reaction mixture was quenched with ice water and extractedwith EtOAc (3×100 mL). The combined organic layer was washed with water(3×100 mL). The organic layer was dried over anhydrous sodium sulfateand concentrated and the residue was crystallized in hexane to obtain115 mg of1-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-2-pyridin-2-yl-propan-2-ol.¹HNMR (CDCl₃, freebase) δ (ppm): 8.51 (d, 1H), 7.65 (t, 1H), 7.29 (d,1H), 7.22 (d, 1H), 7.20 (s, 1H), 6.95 (d, 1H), 6.85 (d, 1H), 4.9 (bs,1H), 4.18 (s, 2H), 3.21 (dd, 2H), 2.77 (m, 2H), 2.69 (m, 2H), 2.42 (d,6H), 1.63 (s, 3H). Separation by chiral HPLC provided enantiomers 16aand 16b. Optical rotations: Compound No. 16a, (−)5.77 (c 0.52,Chloroform, 98.11% HPLC purity); Compound No. 16b, (+)5.85 (c 0.51,Chloroform, 98.06% HPLC purity).

Example 17 Preparation of Compound Nos. 17, 17a and 17b

6,8,8-Trimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene (100 mg,0.465 mmol) was dissolved in DMF (2 mL) and sodium hydride (56 mg, 1.39mmol) was added portionwise under nitrogen. 4-Oxiranyl-pyridine (113 mg,0.933 mmol) was added dropwise at RT and stirred for 12 h. Afterconsumption of starting material (by monitoring TLC and LCMS), thereaction mixture was poured in to ice water and extracted with EtOAc(2×25 mL). The combined organic layer was washed with water (5×10 mL),the organic layer was dried over anhydrous sodium sulfate andconcentrated, and the crude product purified by reverse phasechromatography to obtain 15 mg of1-pyridin-4-yl-2-(6,8,8-trimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-ethanol.¹HNMR (CDCl₃, freebase) δ (ppm): 8.63 (d, 2H), 8.22 (d, 1H), 7.75 (d,1H), 7.45 (d, 2H), 7.09 (dd, 1H), 5.17 (d, 1H), 4.53 (dd, 1H), 4.47 (d,1H), 3.71 (d, 1H), 3.44 (d, 1H), 2.5 (s, 3H), 2.49 (d, 1H), 2.44 (d,1H), 1.47 (s, 3H), 1.32 (s, 3H). Separation by chiral HPLC providedenantiomers 17a and 17b. Optical rotations: Compound No. 17a, (+)50.54(c 0.56, Chloroform, 99.31% HPLC purity); Compound No. 17b, (−)51.38 (c0.55, Chloroform, 95.62% HPLC purity).

Example 18 Preparation of Compound Nos. 18, 18a and 18b

2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (500 mg, 2.5 mmol) wasdissolved in 5 mL DMF and sodium hydride (250 mg, 6.24 mmol) was addedportionwise at 0° C. and the mixture stirred for 10 min.2-(4-Fluoro-phenyl)-oxirane (450 mg, 3.26 mmol) was added dropwise atsame temperature and stirred for 12 h at RT. The reaction was monitoredby TLC & LCMS. After consumption of starting material, the reactionmixture was quenched with ice cold water. The resultant solid wasfiltered and washed with water (100 mL) and hexane (100 mL), and thecrude product was crystallized in EtOH:hexane (5:95 ratio) to obtain 300mg of2-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-1-(4-fluoro-phenyl)-ethanol.¹H NMR (CDCl₃, Free base) δ (ppm): 7.30 (m, 2H), 7.20 (d, 1H), 7.05 (m,3H), 7.0 (d, 1H), 5.0 (t, 1H), 4.05 (d, 2H), 3.62 (d, 1H), 3.30 (d, 1H),2.80 (m, 3H), 2.70 (m, 1H), 2.50 (s, 3H), 2.44 (s, 3H). Separation bychiral HPLC provided enantiomers 18a and 18b. Optical rotations:Compound No. 18a, (−)6.97 (c 0.56, Chloroform, 89.35% HPLC purity);Compound No. 18b, (+)13.03 (c 0.51, Chloroform, 99.51% HPLC purity).

Example 19 Preparation of Compound Nos. 19, 19a and 19b

2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (500 mg, 2.5 mmol) wasdissolved in 10 mL DMF and stirred for 10 min at 0° C. Sodium hydride(300 mg, 7.5 mmol) was added portionwise at RT and stirred for 10 min.4-(2-Methyl-oxiranyl)-pyridine (472 mg, 3.5 mmol) was added dropwise atthe same temperature and stirred for 4 h at RT. The reaction wasmonitored by TLC & LCMS. After consumption of starting material, thereaction mixture was quenched with ice water and extracted with EtOAc(2×60 mL). The combined organic layer was washed with water (5×75 mL),dried over anhydrous sodium sulfate and concentrated and the residue wascrystallized in EtOH and hexane to obtain 175 mg of1-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-2-pyridin-4-yl-propan-2-ol.¹H NMR (CDCl₃, Free base) δ (ppm): 8.58 (d, 2H), 7.40 (d, 2H), 7.25 (s,1H), 7.16 (d, 1H), 6.92 (d, 1H), 4.18-4.0 (dd, 2H), 3.50-3.38 (dd, 2H),2.80 (m, 2H), 2.70 (m, 2H), 2.44 (s, 3H), 2.42 (s, 3H), 1.58 (s, 3H).Separation by chiral HPLC provided enantiomers 19a and 19b. Opticalrotations: Compound No. 19a, (+)22.35 (c 0.58, Chloroform, 98.36% HPLCpurity); Compound No. 19b, (−)22.43 (c 0.55, Chloroform, 99.09% HPLCpurity).

Example 20 Preparation of Compound Nos. 20, 20a and 20b

2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (1.0 g, 5.0 mmol) wasdissolved in 15 mL DMF and sodium hydride (600 mg, 15 mmol) was addedportionwise at 0° C. and stirred for 10 min.2-(4-Methoxy-phenyl)-oxirane (900 mg, 6.0 mmol) was added dropwise atthe same temperature and stirred for 12 h at RT. The reaction wasmonitored by TLC & LCMS. After consumption of starting material, thereaction mixture was quenched with ice cold water and filtered through aCelite bed. A cake of compound was formed which was dissolved in MeOHand DCM. This was again filtered through a Celite bed and the filtrateconcentrated. The solid thus obtained was crystallized in ether & hexaneto get 600 mg of2-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-1-(4-methoxy-phenyl)-ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 7.27 (m, 3H), 7.24 (d, 1H), 7.00 (d,1H), 6.98 (d, 2H), 4.98 (t, 1H), 4.09 (d, 2H), 3.81 (s, 3H), 3.67 (d,1H), 3.32 (d, 1H), 2.79 (m, 3H), 2.7 (m, 1H), 2.49 (s, 3H), 2.45 (s,3H). Separation by chiral HPLC provided enantiomers 20a and 20b. Opticalrotations: Compound No. 20a, (−)10.20 (c 0.58, Chloroform, 99.61% HPLCpurity); Compound No. 20b, (+)10.00 (c 0.59, Chloroform, 96.54% HPLCpurity).

Example 21 Preparation of Compound Nos. 21, 21a and 21b

2-(8-Methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-3-yl)ethanol(1.6 g) was dissolved in acetone (40 mL) followed by the addition ofpotassium carbonate (2.16 g) and 2-bromoethanol (1.29 g). The reactionmixture was heated at 80° C. for 2 h. The reaction was monitored by TLCand LCMS. The reaction mixture was cooled to RT and evaporated underreduced pressure. The residue was diluted with water and extracted withDCM, dried over anhydrous sodium sulfate, and evaporated under reducedpressure to obtain crude product. The crude product was purified byreverse phase column chromatography to obtain desired product. ¹H NMR(CDCl₃, freebase) δ (ppm): 8.33 (d, 1H), 8.24 (s, 1H), 7.56 (d, 1H),7.16 (m, 2H), 7.11 (s, 1H), 6.99 (d, 1H), 4.82 (dd, 1H), 4.03 (dd, 1H),3.98 (dd, 1H), 3.75 (d, 1H), 3.70 (m, 2H), 3.64 (d, 1H), 2.90 (m, 3H),2.74 (m, 2H), 2.5 (dd, 1H), 2.44 (s, 3H). Separation by chiral HPLCprovided enantiomers 21a and 21b. Optical rotations: Compound No. 21a,(−)12.41 (c 0.56, Chloroform, 97.75% HPLC purity); Compound No. 21b,(+)12.71 (c 0.56, Chloroform, 97.37% HPLC purity).

Example 22 Preparation of Compound Nos. 22, 22a and 22b

Sodium hydride (54 mg, 2.2 mmol) was dissolved in N,N-dimethylformamide(7.5 mL) and stirred for 10 min.2,6-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (150 mg, 0.75mmol) was added to the solution and stirred for 10 min, followed byaddition of 2-(oxiran-2-yl)pyridine (133 mg, 1.1 mmol) and stirredovernight at RT. The progress of the reaction was monitored by TLC andLCMS. The reaction mixture was quenched with ice water, extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified by reverse phase chromatography to get puretitle compound as the TFA salt (27 mg). ¹H NMR (DMSO) δ (ppm):10.30-10.10 (m, 1H), 8.70-8.55 (m, 1H), 7.95-7.50 (m, 2H), 7.45-7.05 (m,2H), 7.00-6.75 (m, 2H), 4.95-4.70 (m, 1H), 4.60-4.40 (m, 2H), 4.20-3.60(m, 4H), 3.55-3.35 (m, 2H), 3.00 (s, 3H), 2.38 (s, 3H). Separation bychiral HPLC provided enantiomers 22a and 22b. Optical rotations:Compound No. 22a, (−)58.57 (c 0.57, Chloroform, 98.5% HPLC purity);Compound No. 22b, (+)31.73 (c 0.52, Chloroform, 96.24% HPLC purity).

Example 23 Preparation of Compound Nos. 23, 23a and 23b

To a stirred solution of2-(2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-8-yl) propan-2-ol(942 mg, 3.86 mmol) in DMF (5 mL) was added sodium hydride (60%, 464 mg,11.58 mmol). After stirring for 10 min, the reaction mixture was cooledto 0° C. and a solution of 4-(oxiran-2-yl)pyridine (700 mg, 5.8 mmol) inDMF (2 mL) was added. The reaction mixture was allowed to warm to RT andstirring was continued for 16 h. The progress of reaction was monitoredby LCMS and NMR. The reaction mixture was quenched with ice water andextracted with EtOAc. The organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue obtained was crystallized from ether to yield2-(2,3,4,5-tetrahydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-2-methyl-1H-pyrido[4,3-b]indol-8-yl)propan-2-ol (500 mg) as yellow solid. ¹H NMR (CDCl₃, freebase) δ (ppm):8.37 (d, 2H), 7.36 (s, 1H), 7.20 (d, 1H), 7.11 (d, 2H), 7.04 (d, 1H),4.82 (t, 1H), 4.05 (d, 2H), 3.49 (d, 1H), 3.4 (d, 1H), 2.9 (m, 1H), 2.85(m, 1H), 2.64 (m, 2H), 2.40 (s, 3H), 1.65 (s, 6H). Separation by chiralHPLC provided enantiomers 23a and 23b. Optical rotations: Compound No.23a, (−)52.54 (c 0.55, Chloroform, 95.4% HPLC purity); Compound No. 23b,(+)29.08 (c 0.56, Chloroform, 98.94% HPLC purity).

Example 24 Preparation of Compound Nos. 24, 24a and 24b

To a solution of carboline (320 mg, 1.49 mmol) in DMF (4 mL) was addedsodium hydride (169 mg, 4.23 mmol). After stirring for 5 min, a solutionof 3-(2-methyloxiran-2-yl)pyridine (285 mg, 2.11 mmol) in DMF was addedto the reaction mixture, which was stirred at RT for 16 h. The reactionmixture was quenched with ice-water and extracted with EtOAc. Theorganic layer was dried over anhydrous sodium sulfate, concentrated andresidue obtained was submitted for reverse phase HPLC purification. ¹HNMR (CDCl₃, freebase) δ (ppm): 8.72 (s, 1H), 8.52 (d, 1H), 7.69 (d, 1H),7.21 (m, 3H), 6.95 (d, 1H), 4.21 (q, 2H), 4.00 (s, 2H), 3.11 (t, 2H),2.48 (m, 2H), 2.43 (s, 3H), 1.65 (s, 3H). Separation by chiral HPLCprovided enantiomers 24a and 24b. Optical rotations: Compound No. 24a,(+)25.89 (c 0.58, Chloroform, 96.39% HPLC purity); Compound No. 24b,(−)26.65 (c 0.56, Chloroform, 93.46% HPLC purity).

Example 25 Preparation of Compound Nos. 25, 25a and 25b

To an ice-cooled stirred solution of the Boc protected ester (75 mg) inDCM (1 mL) was added cold 20% TFA-DCM solution (5 mL). After stirringfor 30 min at 0° C., the reaction mixture was stirred at RT for 2 h. Thesolvent was removed under reduced pressure to yield title compound asthe TFA salt. HPLC provided enantiomers 25a and 25b. Compound No. 25a:¹H NMR (CD₃OD, Di-TFA salt) δ (ppm): 8.74 (t, 2H), 7.84 (t, 2H), 7.29(s, 1H), 7.03 (t, 1H), 6.4 (m, 1H), 4.66 (m, 3H), 4.32 (d, 1H), 3.98 (m,2H), 3.5 (m, 1H), 3.2 (m, 1H), 3.11 (s, 3H), 3.06 (m, 1H), 2.4 (s, 3H),2.38 (m, 1H), 0.95 (d, 3H), 0.91 (d, 3H). Compound No. 25b: ¹H NMR(CD₃OD, Di-TFA salt) δ (ppm): 8.806 (d, 2H), 8.05 (t, 2H), 7.63 (t, 1H),7.03 (d, 1H), 6.35 (s, 1H), 4.66 (m, 3H), 4.32 (m, 1H), 4.12 (dd, 1H),3.97 (m, 1H), 3.59 (m, 1H), 3.30 (m, 2H), 3.27 (s, 3H), 3.25 (m, 1H)2.41 (s, 3H), 1.95 (m, 1H), 0.88 (d, 3H), 0.59 (d, 3H).

Example 26 Preparation of Compound Nos. 26, 26a, 26b, 26c and 26d

To a stirred solution of 6-aza-8-methyl tetracyclic carboline (320 mg,1.4 mmol) in DMF (4 mL) was added sodium hydride (169 mg, 4.2 mmol).After stirring for 5 min, a solution of 3-(2-methyloxiran-2-yl)pyridine(285 mg, 2.14 mmol) in DMF (1 mL) was added and the reaction mixturestirred at RT for 16 h. The progress of reaction was monitored by TLCand LCMS. The reaction mixture was quenched with ice-water and extractedwith EtOAc. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified byreverse phase HPLC to yield title compound (574 mg). ¹H NMR (CDCl₃,freebase) δ (ppm): 8.64 (s, 1H), 8.42 (d, 1H), 8.03 (s, 1H), 7.7 (d,1H), 7.53 (s, 1H), 7.14 (dd, 1H), 4.45 (d, 1H), 4.26 (d, 2H), 4.14 (t,1H), 3.25 (d, 1H), 3.01 (m, 1H), 2.84 (m, 1H), 2.63 (q, 1H), 2.46 (m,2H), 2.42 (s, 3H), 2.34 (m, 1H), 1.85 (m, 2H), 1.68 (m, 1H), 1.64 (s,3H). Separation by chiral HPLC provided enantiomers 26a, 26b 26c and26d.

Example 27 Preparation of Compound Nos. 27, 27a and 27b

To a solution of5-(2-azido-2-(pyridin-4-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(2.4 g, 6.93 mmol) in EtOH-water (25-2.5 mL) were added zinc dust (1.8g, 27.7 mmol) and ammonium chloride (1.5 g, 27.74 mmol) and the reactionmixture stirred at 80° C. for 45 min. The reaction mixture was filteredand the filtrate was concentrated under reduced pressure. The residuewas basified with aq. ammonia and extracted with EtOAc. The organiclayer was dried over anhydrous sodium sulfate and evaporated to yield2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanamine(1.2 g). ¹H NMR (CDCl₃, freebase) δ (ppm): 8.56 (d, 2H), 7.28 (d, 2H),7.21 (m, 2H), 7.00 (d, 1H), 4.48 (t, 1H), 4.08 (m, 2H), 3.65 (q, 2H),2.83 (m, 2H), 2.72 (m, 1H), 2.56 (m, 1H), 2.53 (s, 3H), 2.44 (s, 3H).Separation by chiral HPLC provided enantiomers 27a and 27b.

Example 28 Preparation of Compound Nos. 28, 28a and 28b

To a stirred solution of6-chloro-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole (550 mg, 2.5mmol) in DMF (5 mL) was added sodium hydride (300 mg, 7.5 mmol). Afterstirring for 5 min, a solution of 3-(2-methyloxiran-2-yl)pyridine (506mg, 3.75 mmol) in DMF (1 mL) was added and the reaction mixture stirredat RT for 16 h. The progress of reaction was monitored by TLC and LCMS.The reaction mixture was quenched with ice-water and extracted withEtOAc. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The solid was crystallized fromether to yield the title compound (300 mg). ¹H NMR (CDCl₃, freebase) δ(ppm): 8.68 (s, 1H), 8.49 (d, 1H), 7.54 (d, 1H), 7.32 (s, 1H), 7.0 (t,1H), 6.94 (s, 1H), 4.10 (d, 1H), 4.04 (d, 1H), 3.59 (d, 1H), 3.34 (d,1H), 2.65 (m, 4H), 2.42 (s, 3H), 1.63 (s, 3H). Separation by chiral HPLCprovided enantiomers 28a and 28b. Optical rotations: Compound No. 28a,(+)26.78 (c 0.54, Chloroform, 98.11% HPLC purity); Compound No. 28b,(−)20.39 (c 0.59, Chloroform, 93.42% HPLC purity).

Example 29 Preparation of Compound Nos. 29, 29a and 29b

A mixture of compound2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (1.5 g, 7.5 mmol,1 equiv.) and NaH (252 mg, 10.5 mmol, 1.4 equiv.) in DMF (30 mL) wereheated to 120° C. for 1 h. The reaction mixture was cooled to RT and2-methyl-5-(2-methyloxiran-2-yl)pyridine (2.46 g, 16.5 mmol, 2.2 equiv.)in DMF (17 mL) was added dropwise over 12 min. The temperature was againraised to 120° C. and stirred for 3 h. The reaction mixture was cooledto RT and water (5 mL) was added, diluted with EtOAc (700 mL) and theorganic layer was washed with water (3×100 mL) and then with brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Thecompound was purified by column chromatography over 230-400 mesh silicagel using a gradient of 10-20% MeOH in EtOAc. Yield: 2.3 g (87%). ¹H NMR(DMSO-d6, oxalate salt) δ (ppm): 8.52 (bs, 1H), 7.73-7.71 (d, 1H),7.31-7.29 (d, 1H), 7.17-7.15 (m, 2H), 6.88-6.86 (d, 1H), 4.34 (bs, 2H),4.24-4.40 (dd, 2H), 3.47 (bs, 2H), 2.98 (bs, 2H), 2.91 (s, 3H), 2.42 (s,3H), 2.35 (s, 3H), 1.48 (s, 3H). Separation by chiral HPLC providedenantiomers 29a and 29b.

Example 30 Preparation of Compound Nos. 30, 30a and 30b

Activated magnesium turnings (480 mg, 20 g/atom) and 2-3 crystals ofiodine were stirred under anhydrous conditions. The excess of iodine wasremoved by heating with a heat gun. The magnesium turnings were nowyellow in color. To this was added diethyl ether (15 mL) at 0° C. andstirred for 15 min. (until the color of the magnesium becomes white). Tothis was added cyclopentyl bromide (480 mg, 20 g/atom) dropwise withconstant stirring. The reaction mixture was stirred until a darkgrey-colored solution was obtained. Into a separate flask was placed thestarting material2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanone(168 mg, 5 mmol) in THF under anhydrous conditions. The solution of theprepared cyclopentylmagnesium bromide (5 mL) was added dropwise. Afteraddition, the mixture was allowed to come to RT and stirred at RT for 2h. The reaction was monitored by TLC and NMR. The reaction was quenchedwith ice water and the product extracted into EtOAc. The organicextracts were concentrated and the residue purified by silica gel columnchromatography (#100-200 mesh) using 0-3% MeOH:DCM as eluent. (Note: Thedesired compound was not formed but reduction of keto group occurred toyield the hydroxy compound). ¹H NMR (DMSO-d6, oxalate salt) δ (ppm):7.55 (m, 3H), 7.18 (m, 3H), 6.95 (d, 1H), 4.85 (s, 1H), 4.30 (m, 2H),4.15 (m, 2H), 3.60 (m, 2H), 3.10 (m, 3H), 2.90 (s, 3H), 2.40 (s, 3H).Separation by chiral HPLC provided enantiomers 30a and 30b.

Example 31 Preparation of Compound Nos. 31, 31a and 31b

Sodium hydride (1-3 equiv.) was added to a solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.0 equiv.)in DMF, and heated to 120° C. for 1 h with stirring. The reactionmixture was cooled to 0° C. and 3-(2-methyloxiran-2-yl)pyridine (2-7.5equiv.) was added dropwise over 5 min. The temperature was raised to120° C. and stirred for 2 h. The reaction mixture was cooled to RT andpartitioned between EtOAc and water. The organic layer was separated andthe aqueous layer was extracted with EtOAc. The combined organic layerswere washed with water and followed by brine, dried over anhydroussodium sulfate and concentrated under vacuum to provide the crudeproduct. The product was purified by flash column chromatography oversilica gel (230-400 mesh, deactivated with 1% triethylamine/hexane)using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The purecompound was converted to its oxalate salt. The analytical sample wasprepared by dissolving free base in THF and treatment with 1 equiv. ofoxalic acid dihydrate. ¹H NMR (CD₃OD, oxalate salt) δ (ppm): 8.43 (s,1H), 8.34 (d, 1H), 7.87 (d, 1H), 7.37 (s, 1H), 7.30 (m, 1H), 6.97 (m,1H), 6.93 (d, 1H), 4.48 (m, 2H), 4.32 (m, 2H), 3.71 (m, 2H), 3.12 (s,3H), 2.81 (m, 2H), 1.70 (s, 3H). Separation by chiral HPLC providedenantiomers 31a and 31b.

Example 32 Preparation of Compound Nos. 32, 32a and 32b

A flask was charged with6-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 4.5mmol) in DMF (10 mL) and stirred for 5 min. To this was added NaH (60%in hexane) (220 mg, 6.8 mmol) and stirred at RT for 10 min., followed by4-(2-methyloxiran-2-yl)pyridine (1.08 g, 9 mmol) and stirred at RT for16 h. The progress of reaction was monitored by TLC. The mixture waspoured into ice water and filtered. The filtrate was washed with waterand concentrated. The residue was recrystallized from ether to get pureproduct. ¹H NMR (DMSO-d6, HCl salt) δ (ppm): 8.70 (d, 2H), 7.90 (d, 2H),7.40 (m, 1H), 7.0 (m, 2H), 6.0 (m, 1H), 4.80 (m, 1H), 4.60 (m, 2H), 4.25(m, 2H), 3.80 (m, 2H), 2.90 (s, 3H), 1.60 (s, 3H). Separation by chiralHPLC provided enantiomers 32a and 32b.

Example 33 Preparation of Compound Nos. 33, 33a and 33b

8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1.3 g, 5mmol) was dissolved in DMF (10 mL) and stirred for 5 min. Sodium hydride(709 mg, 17.7 mmol) was then added to it portionwise under nitrogen.This was followed by addition of 2-butyl-2-(4-fluorophenyl)oxirane (3.4g, 17.7 mmol) at RT and the reaction mixture was stirred for 18 h. Aftercompletion of reaction, the reaction mixture was poured into ice waterand the product extracted with EtOAc. The organic layer was washed withwater, dried over anhydrous sodium sulfate and concentrated underreduced pressure to give the crude product which was purified by silicagel (#100-200 mesh) column chromatography using 1% MeOH in DCM aseluent. The pure compound was converted into the oxalate salt. ¹HNMR(CDCl₃, Oxalate salt) δ (ppm): 7.30 (m, 3H), 7.10 (d, 1H), 6.95 (m, 3H),4.20 (m, 1H), 4.0 (m, 1H), 3.62 (m, 2H), 2.70 (m, 3H), 2.50 (s, 3H),2.20 (m, 1H), 2.0 (m, 1H), 1.80 (m, 1H), 1.22 (m, 3H), 1.0 (m, 1H), 0.80(t, 3H). Separation by chiral HPLC provided enantiomers 33a and 33b.

Example 34 Preparation of Compound Nos. 34, 34a and 34b

2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanone(168 mg, 5 mmol) was dissolved in 10 mL anhydrous THF. Ethyl magnesiumbromide (1.5 mL, 0.0015 mol) was then added dropwise at RT undernitrogen. The reaction mixture was stirred at RT for 2 h. The reactionwas monitored by LCMS. On completion of the reaction, water (3 mL) wasadded to the reaction mixture and the product extracted with EtOAc (3×).The combined organic layers were washed with water, dried over anhydroussodium sulfate, and the solvent evaporated under reduced pressure toobtain the crude product, which was purified by HPLC. The pure compoundwas isolated as the TFA salt. ¹HNMR (CD₃OD, TFA salt) δ (ppm): 7.38 (m,2H), 7.18 (d, 1H), 7.10 (m, 1H), 7.0 (m, 2H), 6.85 (d, 1H), 4.60 (m,1H), 4.30 (m, 2H), 3.75 (m, 1H), 3.42 (m, 1H), 3.10 (s, 3H), 2.90 (m,2H), 2.42 (d, 1H), 2.38 (s, 3H), 2.20 (m, 1H), 1.80 (m, 2H), 0.8 (t,3H). Separation by chiral HPLC provided enantiomers 34a and 34b.

Example 35 Preparation of Compound Nos. 35, 35a and 35b

A flask was charged with sodium hydride (0.640 g, 50-60%) in dry DMF (10mL) at 0° C. and to this was added2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (0.8 g). Themixture was stirred at RT for 30 min and then4-(2-ethyloxiran-2-yl)pyridine (0.834 g) dissolved in DMF (2 mL) wasadded, which was stirred at RT for 12 h. The reaction mixture wasdiluted with ice-water and extracted with EtOAc (3×30 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate and evaporated. The crude product was triturated with diethylether to obtain the desired compound. ¹HNMR (DMSO, Oxalate salt) δ(ppm): 8.45 (d, 2H), 7.42 (d, 2H), 7.30 (d, 1H), 7.10 (s, 1H), 6.82 (d,1H), 4.30 (d, 1H), 4.18 (d, 1H), 3.60 (s, 2H), 3.50 (m, 2H), 3.38 (m,1H), 3.0 (m, 2H), 2.90 (s, 3H), 3.32 (s, 3H), 2.10 (m, 1H), 0.6 (t, 3H).Separation by chiral HPLC provided enantiomers 35a and 35b.

Example 36 Preparation of Compound Nos. 36, 36a-36d

To a solution of1-ethyl-7-methyl-3,4,5,10-tetrahydro-1H-2,5-methanoazepino[3,4-b]indole(1000 mg, 4.17 mmol) in DMF (10 mL) was added sodium hydride (500 mg,12.498 mmol) portionwise. After stirring at RT for 5 min,4-(oxiran-2-yl)pyridine (630 mg, 5.00 mmol) was added dropwise into thereaction mixture, which was stirred at RT overnight. The reactionmixture was quenched with ice-water and the solid mass was filtered. Theresidue was washed with water (2×10 mL), hexane (2×50 mL) and purifiedby reverse phase HPLC to yield the title compound. Separation by chiralHPLC provided enantiomers 36a and 36b.

Example 37 Preparation of Compound Nos. 37, 37a, 37c and 37d

To a solution of2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-cyclopenta[b]fluorene (1 g,0.0046 mol) in DMF (20 mL) was added NaH (60%, 0.552 g, 0.0138 mol)portionwise followed by 4-(oxiran-2-yl)pyridine (0.709 g, 0.0056 mol).The reaction mixture was stirred at RT overnight. The progress ofreaction mixture was monitored by LCMS. The reaction mixture wasquenched with ice cold water (300 mL) and extracted with EtOAc (3×100mL). The combined organic layer was washed with water (10×100 mL)followed by brine (2×100 mL), dried over anhydrous sodium sulfate andconcentrated. The residue was purified by silica gel columnchromatography followed by reverse phase HPLC to obtain the desiredcompound. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.56 (d, 2H), 8.21 (d, 1H),7.74 (d, 1H), 7.32 (d, 2H), 7.06 (dd, 1H), 5.16 (dd, 1H), 4.44 (dd, 1H),4.31 (dd, 1H), 4.2 (d, 1H), 3.32 (m, 2H), 2.85 (d, 1H), 2.5 (m, 1H),2.39 (q, 2H), 2.11 (m, 1H), 1.93 (m, 2H). Separation by chiral HPLCprovided enantiomers 37a, 37b, 37c and 37d.

Example 38 Preparation of Compound Nos. 38, 38a-38h

To a solution of1,7-dimethyl-3,4,5,10-tetrahydro-1H-2,5-methanoazepino[3,4-b]indole (1g, 4.42 mmol) in DMF (10 mL) was added sodium hydride (530 mg, 13.24mmol) portionwise under nitrogen. After stirring for 10 min at 0° C.,4-oxiranyl-pyridine (1.07 g, 8.84 mmol) was added dropwise at 0° C. intothe reaction mixture and stirring continued for 12 h at RT. Aftercompletion, the reaction mixture was poured into ice water and extractedwith EtOAc (2×100 mL). The combined organic layers were washed withwater (5×50 mL), dried over anhydrous sodium sulfate and concentrated toobtain 1.2 g of product. ¹H NMR (CD₃OD, Formate salt) δ (ppm): 8.42 (d,2H), 7.8 (d, 2H), 7.22 (s, 1H), 6.78 (t, 2H), 5.67 (q, 1H), 5.4 (m, 1H),4.77 (dd, 1H), 4.4 (dd, 1H), 3.82 (d, 1H), 3.7-3.8 (m, 3H), 3.6 (d, 1H),2.4 (m, 1H), 2.3 (s, 3H), 2.18 (m, 1H), 1.97 (d, 3H). Separation bychiral HPLC provided enantiomers 38a and 38b.

Example 39 Preparation of Compound Nos. 39, 39a and 39b

2-(2-Allyl-8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol(740 mg, 2.132 mmol) was dissolved in 40 mL DCM, and purged withnitrogen for 5 min. Pd(PPh₃)₄ (50 mg, 0.0432 mmol) and1,3-dimethylbarbituric acid (998 mg, 6.397 mmol) were added and thereaction mixture was stirred at RT for 30 min. The reaction mixture wasdiluted with saturated aqueous potassium carbonate (20 mL) solution andextracted with DCM (2×20 mL). The combined organic layer was dried overanhydrous sodium sulfate and concentrated. The residue was purified bycolumn chromatography over neutral alumina (eluent 50% MeOH in DCM) toobtain 400 mg of2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol.¹H NMR (CD₃OD, freebase) δ (ppm): 8.71 (d, 2H), 8.04 (d, 2H), 7.22 (s,1H), 7.13 (d, 1H), 6.94 (d, 1H), 5.33 (t, 1H), 4.42 (m, 4H), 3.63 (t,2H), 3.28 d (t, 1H), 3.22 (m 1H), 2.38 (s, 3H). This racemate wasseparated by chiral semi-preparative HPLC to obtain enantiomers 39a and39b.

Example 40 Preparation of Compound Nos. 40, 40a and 40b

To a solution of2-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(500 mg, 1.96 mmol) in DMF (5 mL) was added sodium hydride (60%, 236 mg,5.9 mmol) at RT under N₂. After stirring for 10 min, a solution of3-(oxiran-2-yl)pyridine (356 mg, 2.9 mmol) in DMF (1 mL) was added intothe reaction mixture, which was stirred at RT for 16 h. The progress ofreaction was monitored by TLC, LCMS and NMR. After completion, thereaction mixture was quenched with ice water and extracted with EtOAc.The organic layer was washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by reverse phase HPLC to obtain the desired compounds 40a and40b.

Example 41 Preparation of Compound Nos. 41, 41a and 41b

To a solution of6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.0 g, 4.55mmol) in DMF (20 mL), sodium hydride (546 mg, 13.65 mmol) was added andthe suspension stirred at RT for 10 min. A solution of4-(oxiran-2-yl)pyridine (1.10 g, 9.1 mmol) in DMF (5 mL) was addedslowly into the reaction mixture, which was stirred at RT overnight. Theprogress of reaction was monitored by TLC and LCMS. The reaction masswas poured into ice cold water (200 mL) slowly and extracted with EtOAc(3×200 mL). The organic layer was washed with water (4×300 mL), driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby silica gel column chromatography using 7% MeOH-DCM as eluent. Theresidue obtain was triturated with diethyl ether (20 mL) to yield thedesired product. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.42-8.58 (d, 2H),7.4 (s, 1H), 7.26 (d, 2H), 7.15 (d, 1H), 7.11 (d, 1H), 4.9 (dd, 1H),4.08 (dd, 1H), 4.04 (dd, 1H), 3.73 (d, 1H), 3.48 (s, 1H), 3.3 (d, 1H),2.69 (m, 1H), 2.68 (m, 3H), 2.45 (s, 3H). Separation by chiral HPLCprovided enantiomers 41a and 41b.

Example 42 Preparation of Compound Nos. 42, 42a and 42b

1-(2-Allyl-8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyrimidin-4-yl-propan-2-ol(300 mg, 0.785 mmol) was dissolved in DCM (6 mL) and N₂ was purged for 5min into the reaction mixture. 1,3-Dimethylbarbituricacid (367 mg, 2.356mmol) and Pd(PPh₃)₄ (18 mg, 0.0157 mmol) was added and the mixturestirred for 1 h at RT. After consumption of starting material, thereaction mixture was diluted with saturated potassium carbonate (50 mL)and extracted with DCM (2×40 mL). The combined organic layer was driedover anhydrous sodium sulfate and concentrated, crude was purified byreverse phase chromatography to obtain 97 mg of1-(8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyrimidin-4-yl-propan-2-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 9.13 (s, 1H), 8.45 (d, 1H), 7.31 (d,1H), 7.25 (s, 1H), 6.94 (s, 2H), 4.3 (q, 2H), 3.93 (q, 2H), 3.13 (m,2H), 2.78 (d, 1H), 2.57 (d, 1H), 1.6 (s, 3H). Separation by chiral HPLCprovided enantiomers 42a and 42b.

Example 43 Preparation of Compound Nos. 43, 43a and 43b

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(1 g, 5 mmol) in mL DMF, was added sodium hydride (600 mg, 15 mmol)portionwise under nitrogen at 0° C. and stirred for 10 min.3-Oxiranyl-pyridine (908 mg, 15.0 mmol) was added dropwise undernitrogen and the reaction mixture stirred at RT for 12 h. After thecomplete conversion of starting material (TLC and LCMS), the reactionmixture was poured in ice-cold water and extracted with EtOAc (2×100mL). The combined organic layer was washed with water (5×50 mL), driedover anhydrous sodium sulfate, and concentrated. The crude mixture waspurified by reverse phase chromatography to obtain 290 mg of2-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-1-pyridin-3-yl-ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.62 (s, 1H), 8.57 (d, 1H), 7.67 (d,1H), 7.3 (m, 2H), 7.19 (d, 1H), 7.01 (d, 1H), 5.09 (t, 1H), 4.13 (m,2H), 3.70 (d, 1H), 3.36 (d, 1H), 2.79 (m, 3H), 2.703 (m, 1H), 2.5 (s,3H), 2.45 (s, 3H). Separation by chiral HPLC provided enantiomers 43aand 43b.

Example 44 Preparation of Compound Nos. 44, 44a and 44b

Sodium hydride (60%) (555 mg, 13.88 mmol) was added portionwise to asolution of 6-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(1.0 g, 4.629 mmol) in DMF (10 mL) and stirred at RT for 15 min, thesuspension was allowed to cool at 0° C. 4-(Oxiran-2-yl)pyridine (896 mg,7.407 mmol) was added dropwise and reaction mixture was stirred at RTfor 48 h. The reaction mixture was poured in to ice-cooled water andextracted with EtOAc (3×50 mL), and the organic layer was washed withwater (2×50 mL), dried over anhydrous sodium sulfate and concentrated invacuo, afforded crude was purified by reverse phase HPLC to afford2-(6-methoxy-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol(165 mg) as the formate salt. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.60 (d,2H), 7.31 (d, 2H), 7.02 (m, 2H), 6.66 (d, 1H), 5.08 (dd, 1H), 4.66 (dd,1H), 4.12 (dd, 1H), 3.99 (s, 3H), 3.60 (d, 1H), 3.56 (d, 1H), 2.9 (m,1H), 2.81 (m, 1H), 2.72 (m, 1H), 2.64 (m, 1H), 2.55 (s, 3H). Separationby chiral HPLC provided enantiomers 44a and 44b.

Example 45 Preparation of Compound Nos. 45, 45a and 45b

To a stirred solution of6-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1 g, 4.54mmol) in DMF (8 mL) was added sodium hydride (60%, 545 mg, 13.6 mmol).After stirring for 10 min, a solution of 4-(oxiran-2-yl)pyridine (825mg, 6.8 mmol) in DMF (2 mL) was added into the reaction mixture, whichwas stirred at RT for 16 h. The reaction mixture was poured intoice-cold water and extracted with EtOAc. The organic layer was washedwith water, dried over anhydrous sodium sulfate and concentrated underreduced pressure. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.54 (d, 2H), 7.31(d, 2H), 7.19 (d, 1H), 7.11 (d, 1H), 7.01 (t, 1H), 5.04 (dd, 1H), 4.81(dd, 1H), 3.99 (dd, 1H), 3.27 (dd, 2H), 3.11 (m, 1H), 2.84 (m, 1H), 2.51(m, 2H), 2.32 (s, 3H). Separation by chiral HPLC provided enantiomers45a and 45b.

Example 46 Preparation of Compound Nos. 47, 47a, 47b, 47c and 47d

To a solution of11-methyl-1,2,3,4,6,7,8,12c-octahydro-indolo[3,2-a]quinolizine (800 mg,3.33 mmol) in 12 mL DMF was added sodium hydride (400 mg, 13.2 mmol)under nitrogen at RT and stirred for 20 min. 4-Oxiranyl-pyridine (685mg, 5.66 mmol) was added dropwise under nitrogen and the reactionmixture stirred at RT for 18 h. After complete conversion of startingmaterial (TLC and LCMS), the reaction mixture was poured in ice-coldwater and extracted with EtOAc (3×80 mL). The combined organic layer waswashed with water (5×50 mL), dried over anhydrous sodium sulfate,concentrated and the crude product was recrystallized in EtOH (1 mL) andether (50 mL) to obtain 700 mg of desired product. ¹H NMR (CDCl₃,freebase) δ (ppm): 8.53 (d, 2H), 7.36 (s, 1H), 7.21 (d, 2H), 7.12 (d,1H), 6.94 (d, 1H), 4.99 (t, 1H), 4.1 (m, 2H), 3.35 (d, 1H), 3.13 (t,1H), 3.0 (m, 2H), 2.63 (d, 1H), 2.56 (m, 1H), 2.46 (s, 3H), 2.4 (d, 1H),1.8 (d, 1H), 1.7 (m, 1H), 1.5 (m, 2H). Separation by chiral HPLCprovided enantiomers 47a 47b, 47c and 47d.

Example 47 Preparation of Compound Nos. 48, 48a and 48b

To a stirred solution of6-bromo-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (1 g, 3.77mmol) in DMF (8 mL) was added sodium hydride (60%, 452 mg, 11.32 mmol).After stirring for 10 min, a solution of 4-(oxiran-2-yl)pyridine (684mg, 5.66 mmol) in DMF (2 mL) was added into the reaction mixture, whichwas stirred at RT for 16 h. The reaction mixture was poured intoice-cold water and extracted with EtOAc. The organic layer was washedwith water, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was dissolved in DCM and pure productprecipitated out as a white solid. ¹H NMR (CDCl₃, freebase) δ (ppm):8.57 (d, 2H), 7.36 (d, 2H), 7.33 (d, 1H), 7.27 (d, 1H), 6.95 (t, 1H),5.17 (dd, 1H), 4.96 (dd, 1H), 4.04 (dd, 1H), 3.34 (dd, 2H), 3.1 (m, 1H),2.85 (m, 1H), 2.55 (m, 2H), 2.38 (s, 3H). Separation by chiral HPLCprovided enantiomers 48a and 48b.

Example 48 Preparation of Compound Nos. 49, 49a and 49b

To a stirred solution of1-(2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-8-yl)ethanone (80mg, 0.35 mmol) in DMF (2 mL) was added sodium hydride (60%, 42 mg, 1.05mmol). After stirring for 10 min, a solution of 4-(oxiran-2-yl)pyridine(62 mg, 0.51 mmol) in DMF (1 mL) was added into the reaction mixture,and stirred at RT for 4 h. The reaction mixture was quenched with icewater and extracted with EtOAc. The organic layer was washed with water,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue obtain was purified by crystallization with etherto yield1-(2,3,4,5-tetrahydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-2-methyl-1H-pyrido[4,3-b]indol-8-yl)ethanone(6 mg). ¹H NMR (CDCl₃, freebase) δ (ppm): 8.5 (d, 2H), 7.95 (s, 1H),7.73 (d, 1H), 7.26 (d, 2H), 7.12 (d, 1H), 4.78 (t, 1H), 4.8 (d, 2H),3.49 (m, 2H), 2.90 (m, 1H), 2.8 (q, 2H), 2.79 (s, 3H), 2.6 (m, 1H), 2.37(s, 3H). Separation by chiral HPLC provided enantiomers 49a and 49b.

Example 49 Preparation of Compound Nos. 51, 51a and 51b

2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 5.0 mmol)was dissolved in DMF (8 mL). Sodium hydride (600 mg, 15 mmol) was addedportionwise under nitrogen at 0° C. 2-Methoxy-5-oxiranyl-pyridine (1.130g, 7.5 mmol) was diluted in DMF (2 mL) was added dropwise under nitrogenatmosphere and the reaction mixture stirred at RT for 3 h. By monitoringTLC & NMR after consumption of starting material, the reaction mixturewas then quenched with ice water and extracted with EtOAc (3×40 mL). Thecombined organic layer was washed with water (4×30 mL) and dried overanhydrous sodium sulfate and concentrated to obtain 1.0 g of2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(6-methoxy-pyridin-3-yl)-ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.11 (s, 1H), 7.55 (d, 1H), 7.18 (s,1H), 7.16 (d, 1H), 6.98 (d, 1H), 6.72 (d, 1H), 4.98 (t, 1H), 4.11 (m,2H), 3.93 (s, 3H), 3.60 (q, 2H), 2.88 (d, 1H), 2.78 (m, 2H), 2.69 (d,1H), 2.51 (s, 3H), 2.44 (s, 3H). Separation by chiral HPLC providedenantiomers 51a and 51b.

Example 50 Preparation of Compound Nos. 52, 52a and 52b

To a stirred solution of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (250 mg, 1.25mmol) in DMF (5 mL) was added sodium hydride (60%, 150 mg, 3.75 mmol).After stirring for 10 min, a solution of ethyl 4-(oxiran-2-yl)benzoate(480 mg, 2.5 mmol) in DMF (1 mL) was added to the reaction mixture,which was stirred at RT for 16 h. The reaction mixture was quenched withice water and extracted with EtOAc. The organic layer was dried overanhydrous sodium sulfate, evaporated and residue was purified by reversephase HPLC. ¹H NMR (CDCl₃, freebase) δ (ppm): 7.28 (m, 4H), 7.12 (s,1H), 7.04 (d, 1H), 6.88 (d, 1H), 4.91 (t, 1H), 4.09 (d, 2H), 3.58 (q,2H), 3.1 (s, 3H), 2.92 (s, 3H), 2.87 (m, 1H), 2.80 (m, 2H), 2.68 (d,1H), 2.47 (s, 3H), 2.41 (s, 3H). Separation by chiral HPLC providedenantiomers 52a and 52b.

Example 51 Preparation of Compound Nos. 53, 53a and 53b

To a stirred solution of7-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g,2.265 mmol) in anhydrous DMF was added sodium hydride (271 mg, 3 eq.)portionwise followed by 4-(oxiran-2-yl)pyridine (548 mg, 4.5 mmol) atRT. The reaction mixture was stirred for 12 h. The reaction mixture wasquenched with ice water and extracted with EtOAc, the organic layerwashed with water, dried on anhydrous sodium sulfate, concentrated undervacuum to obtain crude product that was triturated with diethyl ether toobtain2-(7-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanolas solid. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.53 (d, 2H), 7.2 (m, 3H),7.14 (d, 1H), 7.05 (d, 1H), 4.82 (t, 1H), 4.03 (d, 2H), 3.4 (q, 2H),2.85 (m, 1H), 2.76 (m, 1H), 2.64 (m, 2H), 2.37 (s, 3H). Separation bychiral HPLC provided enantiomers 53a and 53b.

Example 52 Preparation of Compound Nos. 54, 54a and 54b

To a solution of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol(500 mg, 1.55 mmol) and isobutyric acid (274 mg, 3.1 mmol) in DCM (100mL) were added EDC.HCl (657 mg, 3.4 mmol), DMAP (19 mg, 0.16 mmol) andTEA (346 mg, 3.4 mmol). The reaction mixture was stirred at RT for 16 hand washed with water. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (4% MeOH-DCM) followed byreverse phase purification to yield2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethylisobutyrate (310 mg). ¹H NMR (CDCl₃, freebase) δ (ppm): 8.53 (d, 2H),7.2 (d, 1H), 7.18 (s, 1H), 7.04 (d, 2H), 6.97 (d, 1H), 5.98 (t, 1H), 4.4(dd, 1H), 4.14 (dd, 1H), 3.64 (q, 2H), 2.73 (m, 2H), 2.6 (m, 1H), 2.49(s, 3H), 2.43 (s, 3H), 2.37 (m, 1H), 1.15 (d, 3H), 1.09 (d, 3H).Separation by chiral HPLC provided enantiomers 54a and 54b.

Example 53 Preparation of Compound Nos. 55, 55a and 55b

3,6-Dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene (250 mg, 1.243mmol) was dissolved in DMF (3 mL) and cooled to 0° C. Sodium hydride(149 mg, 3.729 mmol) was added portionwise and the mixture stirred atthe same temperature for 10 min. 4-Oxiranyl-pyridine (240 mg, 1.990mmol) was diluted in DMF (1 mL) and added dropwise in the reactionmixture at 0° C. The reaction mixture was stirred at RT for 12 h. Thedesired product was detected by LCMS. The reaction mixture was poured inice cold water and extracted with EtOAc (3×25 mL). The combined organiclayer was washed with water (5×30 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The crude product waspurified by reverse phase chromatography to obtain 18 mg of2-(3,6-dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-pyridin-4-yl-ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.48 (d, 2H), 7.95 (s, 1H), 7.43 (s,1H), 7.18 (d, 2H) 5.06 (d, 1H), 4.37 (d, 1H), 4.24 (dd, 1H), 3.45 (q,2H), 2.29 (t, 2H), 2.55 (t, 2H), 2.45 (s, 3H), 2.38 (s, 3H). Separationby chiral HPLC provided enantiomers 55a and 55b.

Example 54 Preparation of Compound Nos. 56, 56a and 56b

To a solution of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol(900 mg, 4.5 mmol) in DMF (4 mL) was added sodium hydride (540 mg, 13.5mmol). After stirring for 10 min at RT, a solution of3-(2-methyloxiran-2-yl)pyridine-N-oxide (1 g, 6.75 mmol) was added tothe reaction mixture, and stirred at RT for 16 h. The reaction mixturewas cooled to 0° C., quenched with ice water and extracted with EtOAc.The organic layer was washed with water, dried over anhydrous sodiumsulfate and evaporated. The residue was triturated with ether to yieldthe title compound as yellow solid (220 mg). ¹H NMR (CD₃OD, freebase) δ(ppm): 8.27 (s, 1H), 8.12 (d, 1H), 7.58 (d, 1H), 7.32 (t, 1H), 7.07 (s,1H), 6.94 (d, 1H), 6.79 (d, 1H) 4.14 (q, 2H), 3.63 (s, 2H), 2.88 (m,1H), 2.82 (s, 2H), 2.79 (m, 1H), 2.51 (s, 3H), 2.331 (s, 3H), 1.62 (s,3H). Separation by chiral HPLC provided enantiomers 56a and 56b.

Example 55 Preparation of Compound Nos. 57, 57a and 57b

6-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 4.5mmol) was dissolved in 15 mL DMF and stirred for 5 min at RT. Sodiumhydride (540 mg, 13.5 mmol) was added portionwise at RT under nitrogen.3-(2-Methyl-oxiranyl)-pyridine (800 mg, 5.9 mmol) was diluted in 5 mLDMF and added dropwise at the same temperature and stirred for 16 h atRT. The reaction was monitored by TLC & LCMS. After consumption ofstarting material, the reaction mixture was quenched with ice water (30mL) and filtered. The residue was crystallized in EtOH (1 mL) and ether(40 mL) and purified by reverse phase chromatography to obtain 620 mg of1-(6-chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.77 (s, 1H), 8.5 (d, 1H), 8.45 (s,1H), 7.71 b (s, 1H), 7.17 b (s, 1H), 7.06 (d, 1H), 6.97 (t, 1H), 5.12 b(s, 1H), 4.3 b (s, 1H), 3.78 (m, 1H), 3.62 (m, 1H), 3.14 (m, 1H), 2.63(m, 2H), 2.57 (s, 3H), 2.5 b (s, 2H), 1.53 (s, 3H). Separation by chiralHPLC provided enantiomers 57a and 57b.

Example 56 Preparation of Compound Nos. 58, 58a and 58b

To a degassed solution of2-(6-allyl-3-methyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-pyridin-4-yl-ethanol(300 mg, 0.862 mmol) and 1,3 dimethyl barbituric acid (403 mg, 2.586mmol) in DCM (7 mL) was added and Pd(PPh₃)₄ (20 mg, 0.0172 mmol) and thereaction mixture stirred at RT for 1 h. The progress of reaction wasmonitored by TLC and LCMS. The reaction mixture was diluted with 20% aqpotassium carbonate solution and extracted with DCM (3×25 mL). Thecombined organic layer was washed with 20% aq potassium carbonatesolution, dried over anhydrous sodium sulfate and concentrated to yield2-(3-methyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-pyridin-4-yl-ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.5 (d, 2H), 8.03 (s, 1H), 7.51 (s,1H), 7.22 (d, 2H) 5.14 (d, 1H), 4.4 (dd, 1H), 4.27 (dd, 1H), 3.93 (q,2H), 3.13 (m, 2H), 2.54 (dd, 1H), 2.42 (s, 3H), 2.3 (dd, 1H). Separationby chiral HPLC provided enantiomers 58a and 58b.

Example 57 Preparation of Compound Nos. 59, 59a and 59b

To a solution of2-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(200 mg, 0.78 mmol) in DMF (3 mL) was added sodium hydride (60%, 94 mg,2.3 mmol) at RT under N₂. After stirring for 10 min, a solution of3-(oxiran-2-yl)pyridine (142 mg, 1.17 mmol) in DMF (1 mL) was added intothe reaction mixture, which was stirred at RT for 16 h. The progress ofreaction was monitored by TLC, LCMS and NMR. After completion, thereaction mixture was quenched with ice water and extracted with EtOAc.The organic layer was washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by reverse phase HPLC to obtain the desired compounds. 59a: ¹HNMR (CDCl₃, freebase) δ (ppm): 8.51 (s, 1H), 8.35 (d, 1H), 7.51 (s, 1H),7.42 (d, 1H), 7.32 (d, 1H), 7.21 (d, 1H), 7.07 (t, 1H), 4.94 (t, 1H),4.20 (dd, 1H), 4.09 (dd, 1H), 3.49 (q, 2H), 2.9 (d, 1H), 2.76 (m, 3H),2.41 (s, 3H). 59b: ¹H NMR (CDCl₃, freebase) δ (ppm): 8.51 (s, 1H), 8.35(d, 1H), 7.51 (s, 1H), 7.42 (d, 1H), 7.32 (d, 1H), 7.21 (d, 1H), 7.07(t, 1H), 4.94 (t, 1H), 4.20 (dd, 1H), 4.09 (dd, 1H), 3.49 (q, 2H), 2.9(d, 1H), 2.76 (m, 3H), 2.41 (s, 3H). Separation by chiral HPLC providedenantiomers 59a and 59b. Optical rotations: Compound No. 59a, (−)16.42(c 0.54, Chloroform, 99.96% HPLC purity); Compound No. 59b, (+)11.20 (c0.54, Chloroform, 99.01% HPLC purity).

Example 58 Preparation of Compound No. 60

To a solution of8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.9mmol) in N-methyl-2-pyrolidone (1.5 mL) was added powdered potassiumhydroxide (0.507 g, 9.0 mmol). The reaction mixture was stirred for 10min at RT. 3-Vinyl pyridine (0.3 g, 2.8 mmol) was added and the reactionmixture was stirred at 100° C. for 18 h. After consumption of startingmaterial (TLC), the reaction mixture was diluted with water (15 mL) andextracted with EtOAc (3×100 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product was purified by column chromatography over silica gel(eluent 8% MeOH: DCM) followed by preparative TLC to obtain the desiredcompound as a yellow oil (0.032 g, 11% yield). ¹H NMR (DMSO, Oxalatesalt) δ (ppm): 8.4 (d, 1H), 8.3 (s, 1H), 7.57 (d, 2H), 7.49 (d, 1H),7.26 (m, 1H), 7.10 (d, 1H), 4.45 (m, 4H), 3.5 (bs, 2H), 3.0 (t, 2H),2.95 (m, 2H), 2.90 (s, 3H).

Example 59 Preparation of Compound No. 61

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(0.1 g, 0.49 mmol) in N-methyl-2-pyrrolidone (0.5 mL) was added powderedpotassium hydroxide (0.274 g, 4.9 mmol) and the reaction mixture wasstirred for 10 min at RT. 3-Vinyl pyridine (0.26 g, 2.49 mmol) was addedand stirring was continued for further 18 h at 100° C. After consumptionof starting material (TLC), the reaction mixture was diluted with water(15 mL) and extracted with EtOAc (3×50 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The crude product was purified by silica gel chromatography (eluent 7%MeOH: DCM) followed by preparative TLC, to obtain desired compound asyellow oil (0.040 g, 26% yield). ¹H NMR (DMSO, Oxalate salt) δ (ppm):8.4 (s, 1H), 8.3 (s, 1H), 7.55 (s, 2H), 7.35 (d, 1H), 7.25 (bs, 1H), 7.2(s, 1H), 4.35 (bs, 4H), 3.5 (bs, 2H), 3.0 (m, 2H), 2.9 (m, 5H), 2.45 (s,3H).

Example 60 Preparation of Compound Nos. 62, 62a and 62b

Carboline (500 mg, 2.5 mmol) was dissolved in DMF (5 mL). To thissolution was added NaH (60%, 180 mg, 4.5 mmol) at RT and the reactionmixture was stirred for 10-15 min. after which 3-(oxiran-2-yl)pyridine(450 mg, 3.7 mmol) was added. The reaction mixture was stirred at RT for4 h and the reaction was monitored by LCMS. After completion, thereaction mixture was poured on ice water and extracted with EtOAc. Theorganic layer was dried on sodium sulfate and concentrated under reducedpressure. The residue was purified by HPLC to obtain 420 mg of productas a white solid (TFA salt). TLC (silica gel) 5:95 MeOH:DCM, Rf 0.1 wasobserved. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.60 (d, 2H), 8.20 (bs, 1H),7.85 (bs, 1H), 7.20 (s, 1H), 7.0 (d, 1H), 6.9 (d, 1H), 5.2 (bs, 1H), 4.8(d, 2H), 4.4 (m, 4H), 3.9 (bs, 1H), 3.60 (bs, 2H), 3.10 (s, 3H), 2.40(s, 3H). Separation by chiral HPLC provides enantiomers 62a and 62b.

Example 61 Preparation of Compound Nos. 63, 63a and 63b

2-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol(200 mg. 0.62 mmol) was dissolved in 10 mL DCM and m-CPBA (128 mg, 0.74mmol) was diluted in DCM and added dropwise at RT. After consumption ofstarting material by monitoring TLC & LCMS reaction mixture wascomplete, the mixture was concentrated and the crude product waspurified by reverse phase chromatography, to obtain 120 mg of2-(2,8-dimethyl-2-oxy-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol.Separation by chiral HPLC provided enantiomers 63a and 63b. 63a: ¹H NMR(CD₃OD, TFA salt) δ (ppm): 8.56 (d, 2H), 7.9 (t, 2H), 7.22 (s, 1H), 7.2(d, 1H), 7.0 (d, 1H), 5.23 (dd, 1H), 5.08 (d, 1H), 5.0 (d, 1H), 4.4 (m,2H), 4.2 (d, 2H), 3.68 (s, 3H), 3.44 (m, 1H), 3.3 (m, 1H), 2.4 (s, 3H).63b: ¹H NMR (CD₃OD, Free base) δ (ppm): 8.44 d (2H), 7.38 d (2H), 7.24 d(1H), 7.25 s (1H), 7.00 d (1H), 5.07 t (1H), 4.77 d (1H), 4.56 d (1H),4.27 m (2H), 3.86 t (2H), 3.39 m (1H), 3.34 s (3H), 2.82 d t (1H), 2.4 s(3H).

Example 62 Preparation of Compound Nos. 64, 64a and 64b

2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.5mmol) was dissolved in 5 mL DMF and stirred for 10 min at RT. Sodiumhydride (300 mg, 7.5 mmol) was added portionwise at 0° C. and thereaction mixture was stirred for 10 min.2-Methoxy-5-(2-methyl-oxiranyl)-pyridine (566 mg, 3.75 mmol) was dilutedin DMF (2 mL) and added dropwise at the same temperature and stirred for12 h. After consumption of starting material, the reaction mixture wasquenched with ice water and extracted with EtOAc (3×30 mL). The combinedorganic layer was washed with water (7×30 mL), dried over anhydroussodium sulfate and concentrated. The residue was purified by columnchromatography over silica gel (eluent: 15% MeOH in DCM) and furthercrystallized in ether-hexane to obtain 190 mg of1-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-(6-methoxy-pyridin-3-yl)-propan-2-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.22 (s, 1H), 7.5 (d, 1H), 7.1 (s,1H), 7.0 (d, 1H), 6.83 (d, 1H), 6.5 (d, 1H), 4.1 (m, 2H), 3.91 (s, 3H),3.5 (m, 2H), 2.63-2.81 (m, 4H), 2.41 (s, 3H), 2.39 (s, 3H), 1.58 (s,3H). Separation by chiral HPLC provides enantiomers 64a and 64b.

Example 63 Preparation of Compound Nos. 65, 65a and 65b

To a solution of2-methyl-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(1.0 g, 3.937 mmol) in DMF (5 mL) was added NaH (472 mg, 11.81 mmol) inportions at 0° C. After stirring the reaction mixture at 0° C. for 15min, a solution of 4-(oxiran-2-yl)pyridine (714 mg, 5.90 mmol) in DMF (1mL) was dropwise added into the reaction mixture at the same temperatureand stirring was continued at RT overnight. The progress of reaction wasmonitored by TLC, LCMS and NMR. After consumption of starting material,ice water was added into the reaction mixture and the product wasextracted with EtOAc (3×50 mL). The organic layer was washed with water(5×50 mL), dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by silica gel chromatography to yield2-(2-methyl-7-(trifluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.54 (d, 2H), 7.5 (s, 1H), 7.37 (d,1H), 7.3 (d, 1H), 7.18 (d, 2H), 4.78 (m, 1H), 4.17 (m, 2H), 3.5 (m, 2H),2.8 (m, 1H), 2.7 (m, 2H), 2.63 (m, 1H), 2.4 (s, 3H). Separation bychiral HPLC provides enantiomers 65a and 65b.

Example 64 Preparation of Compound Nos. 66, 66a and 66b

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(1.2 g, 6.0 mmol) in 6 mL DMF, was added sodium hydride (720 mg, 12mmol) under nitrogen at 0° C. and stirred for min.2-(3,4-Dimethoxy-phenyl)-oxirane (2.16 g, 18 mmol) was diluted in DMF (2mL) and added dropwise to the reaction mixture under nitrogenatmosphere. The reaction mixture was stirred at RT for 5 h. Afterconsumption of starting material (TLC and LCMS), the reaction mixturewas poured in ice-cold water and extracted with EtOAc (3×50 mL). Thecombined organic layer was washed with water (5×30 mL) and dried overanhydrous sodium sulfate, concentrated and purified by columnchromatography (silica gel 100-200 mesh, eluent: 6% MeOH in DCM) toobtain 590 mg of1-(3,4-dimethoxy-phenyl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 7.19 (m, 2H), 6.98 (d, 1H), 6.83 (m,2H), 6.78 (s, 1H), 4.98 (t, 1H), 4.1 (m, 2H), 4.83 (s, 3H), 4.8 (s, 3H),3.6 (dd, 2H), 2.68-2.88 (m, 3H), 2.53 (m, 1H), 2.5 (s, 3H), 2.4 (s, 3H).Separation by chiral HPLC provides enantiomers 66a and 66b.

Example 65 Preparation of Compound Nos. 67, 67a and 67b

To a solution of4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzoicacid ethyl ester (800 mg, 2.04 mmol) in 5 mL EtOH was added sodiumhydroxide (327 mg, 8.17 mmol, in 5 mL water) and heated to 65° C. Aftercomplete conversion of starting material (TLC and LCMS), the EtOH andwater were removed under reduced pressure. The crude product was passedthrough HPLC to yield 600 mg of4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzoicacid. ¹H NMR (DMSO, freebase) δ (ppm): 7.79 (d, 2H), 7.29 (s, 1H), 7.17(d, 2H), 7.09 (s, 1H), 6.88 (d, 1H), 5.5 b (s, 1H), 4.82 (t, 1H), 4.12(dd, 1H), 4.06 (dd, 1H), 3.44 (s, 2H), 3.16 (s, 2H), 2.71 (d, 1H), 2.56(m, 2H), 2.36 s (7H). Separation by chiral HPLC provides enantiomers 67aand 67b.

Example 66 Preparation of Compound No. 68

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(145 mg, 0.72 mmol) in DMF (2 mL) was added sodium hydride (87 mg, 2.1mmol). After stirring for 10 min at RT, a solution of4-(oxiran-2-yl)pyridine-N-oxide (149 mg, 1.08 mmol) was added into thereaction mixture, which was stirred at RT for 16 h. The reaction mixturewas cooled to 0° C., quenched with ice water and extracted with EtOAc.The organic layer was washed with water, dried over anhydrous sodiumsulfate and evaporated. The residue was triturated with ether to yieldthe title compound (20 mg). ¹H NMR (CDCl₃, Free base) δ (ppm): 8.2 (d,2H), 7.71 (d, 2H), 7.25 (d, 1H), 6.99 (s, 2H), 5.22 (s, 2H), 3.64 (s,2H), 2.85 (t, 2H), 2.7 (t, 2H), 2.56 (s, 3H), 2.42 (s, 3H).

Example 67 Preparation of Compound Nos. 69, 69a and 69b

To a solution of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol(450 mg, 2.25 mmol) in DMF (2 mL) was added sodium hydride (270 mg, 6.75mmol). After stirring for 10 min at RT, a solution of4-(oxiran-2-yl)pyridine-N-oxide (462 mg, 3.37 mmol) was added into thereaction mixture, and stirred at RT for 16 h. The reaction mixture wascooled to 0° C., quenched with ice water and extracted with EtOAc. Theorganic layer was washed with water, dried over anhydrous sodium sulfateand evaporated. The aqueous layer was also lyophilized to get crudeproduct, which was submitted for reverse phase HPLC purification. (Theorganic layer had the keto compound, and the aqueous layer had thehydroxy compound). ¹H NMR (CDCl₃, freebase) δ (ppm): 7.83 (d, 2H), 7.04(s, 1H), 6.91 (m, 4H), 4.72 (t, 1H), 4.01 (dd, 1H), 3.9 (m, 1H), 3.65(m, 1H), 3.46 (d, 1H), 3.4 (d, 1H), 2.77 (m, 1H), 2.6 (m, 1H), 2.4 (m,1H), 2.39 (s, 6H). Separation by chiral HPLC provided enantiomers 69aand 69b.

Example 68 Preparation of Compound Nos. 70, 70a, 70b, 70c and 70d

To an ice-cooled stirred solution of1-(2,3,4,5-tetrahydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-2-methyl-1H-pyrido[4,3-b]indol-8-yl)ethanone(600 mg, 1.72 mmol) in anhydrous THF (10 mL) was portionwise added LAH(163 mg, 4.3 mmol) and stirred at 0° C. for 30 min. The reaction mixturewas quenched by adding water, 15% NaOH and again water. The reactionmixture was filtered, and the filtrate was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by reverse phase HPLC to yield the title compound. ¹H NMR(CDCl₃, freebase) δ (ppm): 8.45 (d, 2H), 7.3 (d, 1H), 7.19 (d, 2H), 7.14(m, 2H), 4.9 (m, 2H), 4.09 (m, 2H), 3.82 (dd, 1H), 3.7 (dd, 1H), 3.07(m, 2H), 2.9 (m, 1H), 2.7 (d, 1H), 2.57 (s, 3H), 1.51 (d, 3H).Separation by chiral HPLC provides enantiomers 70a, 70b, 70c and 70d.

Example 69 Preparation of Compound Nos. 71, 71a and 71b

2,4,4,8-Tetramethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 gm,4.385 mmol) was dissolved in DMF (8 mL) and sodium hydride (0.526 g,13.15 mmol) was added portionwise under nitrogen. 4-Oxiranyl-pyridine(0.9 g, 7.45 mmol) was diluted in DMF (2 mL) and added dropwise at RTand stirred for 4 h. After consumption of starting material (bymonitoring TLC & LCMS), the reaction mixture was poured in to ice water,product was precipitated and filtered, and the residue was washed withwater & hexane, dried under reduced pressure and crystallized in EtOH(10 mL) and diethyl ether (50 mL) to obtain 900 mg of1-pyridin-4-yl-2-(2,4,4,8-tetramethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.62 (d, 2H), 7.37 (d, 2H), 7.31 (d,1H), 7.19 (s, 1H), 7.01 (d, 1H), 5.22 (t, 1H), 4.32 (d, 1H), 3.6 (d,1H), 3.48 (d, 1H), 2.65 b (s, 1H), 2.44 (s, 3H), 1.47 (s, 3H), 1.28 (s,3H). Separation by chiral HPLC provides enantiomers 71a and 71b.

Example 70 Preparation of Compound Nos. 72, 72a and 72b

To a stirred solution of2-(1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol(300 mg, 0.977 mmol) and triethyl amine (0.18 mL, 1.27 mmol) in DCM (6mL) was added ethyl chloroformate (138 mg, 1.27 mmol), and the reactionmixture stirred at RT for 2 h. The progress of reaction was monitored byTLC and LCMS. The reaction mixture was diluted with DCM and washed withwater. The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH-DCM) to yield ethyl3,4-dihydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-8-methyl-1H-pyrido[4,3-b]indole-2(5H)-carboxylate(170 mg). ¹H NMR (CDCl₃, freebase) δ (ppm): 8.4 (d, 2H), 7.21 (m, 4H),7.0 (d, 1H), 5.03 (t, 1H), 4.6 (m, 2H), 4.21 (m, 4H), 3.78 (m, 2H), 3.6(m, 1H), 2.75 (m, 1H), 2.4 (s, 3H), 1.28 (t, 3H). Separation by chiralHPLC provides enantiomers 72a and 72b.

Example 71 Preparation of Compound Nos. 73, 73a-73d

To a solution of carboline (1 g, 4.4 mmol) in 10 mL DMF, was addedsodium hydride (528 mg, 13.2 mmol) under nitrogen at RT and stirred for5 min. 4-Oxiranyl-pyridine (803 mg, 6.6 mmol) was diluted in DMF andadded dropwise under nitrogen and the reaction mixture stirred at RT for16 h. After the complete conversion of starting material (TLC and LCMS),the reaction mixture was poured in ice-cold water and extracted withEtOAc (3×40 mL). The combined organic layer was washed with water (6×30mL) and dried over anhydrous sodium sulfate, concentrated and crude wascrystallized in EtOH in ether to obtain 1.2 g of desired product. ¹H NMR(CDCl₃, freebase) δ (ppm): 8.59 (d, 1H), 8.58 (d, 1H), 7.38 (d, 1H),7.24 (d, 1H), 7.20 (d, 1H), 7.08 (d, 1H), 7.0 (d, 1H), 5.0 (m, 1H), 4.62(dd, 1H), 4.18 (m, 2H), 4.0 (m, 1H), 2.70 (m, 2H), 2.58 (m, 2H), 2.45(s, 3H), 2.42 (s, 3H), 2.10 (m, 1H), 1.70 (m, 1H). Separation by chiralHPLC provides enantiomers 73a-73d.

Example 72 Preparation of Compound Nos. 74, 74a and 74b

To a solution of10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine(110 mg, 0.484 mmol) in DMF (1 mL) was added a suspension of NaH (60.0mg, 1.45 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solutionof 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (423 mg, 1.45mmol) in DMF (1 mL) was added dropwise into the reaction mixture andstirring continued for another 2 h. The progress of reaction wasmonitored by TLC and LCMS. The reaction mixture was diluted with water(20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washedwith water (3×20 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude material, which waspurified by reverse phase HPLC to yield10-methyl-7-(2-(6-methylpyridin-3-yl)ethyl)-2,3,5,6,7,1c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine.¹H NMR (CD₃OD, Tri-HCl salt) δ (ppm): 8.7 (s, 1H), 8.4 (d, 1H), 8.25 (s,2H), 7.8 (d, 1H), 5.1 (m, 1H), 4.8-4.6 (m, 2H), 3.9-3.7 (m, 3H), 3.4 (m,2H), 3.4-3.2 (m, 2H), 2.9-2.7 (m, 2H), 2.8 (s, 3H), 2.5 (s, 3H),2.3-2.15 (m, 3H). Separation by chiral HPLC provided enantiomers 74a and74b.

Example 73 Preparation of Compound Nos. 75, 75a, 75b, 75c and 75d

To a solution of2-methyl-6,7,8,9,10,12-hexahydro-5H,6aH-indolo[2,3-b]quinolizine (1.0 g,4.16 mmol) in 15 mL DMF, was added sodium hydride (500 mg, 12.49 mmol)under nitrogen at RT and stirred for 20 min. 4-Oxiranyl-pyridine (857mg, 7.08 mmol) was added dropwise under nitrogen and the reactionmixture stirred at RT for 18 h. After the complete conversion ofstarting material (TLC and LCMS), the reaction mixture was poured inice-cold water and extracted with EtOAc (3×80 mL). The combined organiclayer was washed with water (5×50 mL) and dried over anhydrous sodiumsulfate, concentrated and crude was crystallized in EtOH (1 mL) andether (40 mL) to obtain 800 mg of desired product. ¹H NMR (CDCl₃,freebase) δ (ppm): 8.54 (d, 2H), 7.22 (d, 2H), 7.102 (s, 1H), 7.00 (d,1H), 6.92 (d, 1H), 4.78 (t, 1H), 4.02 (m, 2H), 3.81 (d, 1H), 3.26 (d,1H), 2.99 (d, 1H), 2.7 (dd, 1H), 2.5 (d, 1H), 2.43 (s, 3H), 2.23 (m,2H), 1.89 (d, 1H), 1.81 (d, 1H), 1.69 (m, 2H), 1.5 (q, 1H), 1.35 (t,1H). This racemate was separated by semi-preparative chiral HPLCseparation to give enantiomers 75a, 75b, 75c and 75d.

Example 74 Preparation of Compound Nos. 76, 76a, 76b, 76c and 76d

To a solution of7-methyl-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole (200 mg,0.88 mmol) in DMF (2 mL) was added NaH (106 mg, 2.65 mmol). Afterstirring for 5 min, a solution of 4-(oxiran-2-yl)pyridine (161 mg, 1.32mmol) in DMF was added into the reaction mixture, which was stirred atRT for 16 h. The reaction mixture was quenched with ice-water andextracted with EtOAc. The organic layer was dried over anhydrous sodiumsulfate, concentrated and the residue obtained was purified by reversephase HPLC to yield the title compound. 76a: ¹H NMR (CDCl₃, freebase) δ(ppm): 8.6 (d, 2H), 7.26 (d, 2H), 7.21 (s, 1H), 7.15 (d, 1H), 7.0 (d,1H), 5.0 (dd, 1H), 4.2 (m, 3H), 3.29 (m, 2H), 2.7 (s, 2H), 2.42 (s, 3H),2.4 (q, 1H), 2.1 (m, 1H), 2.0 (m, 1H), 1.85 (m, 1H), 1.62 (m, 2H). 76b:¹H NMR (CDCl₃, freebase) δ (ppm): 8.53 (d, 2H), 7.24 (d, 2H), 7.17 (s,1H), 7.14 (d, 1H), 6.97 (d, 1H), 4.95 (d, 1H), 4.10 (m, 3H), 3.28 (m,2H), 3.0 (d, 1H), 2.49 (m, 2H), 2.44 (s, 3H), 2.37 (q, 1H), 2.11 (m,1H), 1.97 (m, 1H), 1.87 (m, 1H), 1.63 (m, 1H). 76c: ¹H NMR (CDCl₃,freebase) δ (ppm): 8.5 (d, 2H), 7.17 (d, 2H), 7.06 (s, 1H), 6.97 (d,1H), 6.9 (d, 1H), 4.76 (t, 1H), 4.0 (m, 2H), 3.9 (d, 1H), 3.19 (d, 1H),3.13 (t, 1H), 2.67 (q, 2H), 2.42 (s, 3H), 2.39 (m, 1H), 2.28 (q, 1H),2.08 (t, 1H), 1.93 (m, 1H), 1.86 (m, 1H), 1.64 (m, 1H). 76d: ¹H NMR(CDCl₃, freebase) δ (ppm): 8.53 (d, 2H), 7.24 (d, 2H), 7.17 (s, 1H),7.14 (d, 1H), 6.97 (d, 1H), 4.95 (d, 1H), 4.10 (m, 3H), 3.28 (m, 2H),3.0 (d, 1H), 2.49 (m, 2H), 2.44 (s, 3H), 2.37 (q, 1H), 2.11 (m, 1H),1.97 (m, 1H), 1.87 (m, 1H), 1.63 (m, 1H).

Example 75 Preparation of Compound No. 77

A solution of5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.29 mmol), 1H-pyrazole-4-boronic acid (75 mg, 0.580 mmol) andpotassium carbonate (120 mg, 0.87 mmol) in 1,2-DME (4 mL)-water (2 mL)was purged with nitrogen. Pd(PPh₃)₄ (16 mg, 0.0147 mmol) was added andthe reaction mixture was heated at 90° C. for 45 min. The reactionmixture concentrated under vacuum, residue diluted with water (20 mL)and extracted with EtOAc (50 mL). The organic layer was dried overanhydrous sodium sulfate, concentrated under vacuum to obtain crudewhich was purified by reverse phase HPLC to yield5-(2-(1H-pyrazol-4-yl)cyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.38 (s, 1H), 7.0 (m, 2H), 6.4 (m,2H), 4.7 (m, 1H), 4.4 (m, 1H), 3.78 (m, 1H), 3.42 (m, 1H), 3.11 (m, 4H),2.6-3.0 (m, 5H), 2.4 (s, 3H), 2.2 (m, 2H).

Example 76 Preparation of Compound No. 78

To a degassed solution of3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene (201 mg, 1.00mmol), potassium phosphate (466 mg, 2.20 mmol), L-proline (19 mg, 0.10mmol) and copper iodide (23 mg, 0.20 mmol) in DMF (2 mL) was added4-(2-bromo-1-methyl-vinyl)-pyridine (424 mg, 2.00 mmol). The reactionmixture was stirred at 120° C. for 20 h. The progress of reaction wasmonitored by TLC and LCMS. The reaction was monitored by TLC and LCMS.The reaction mixture was diluted with water (20 mL) and extracted withEtOAc (3×10 mL). The organic layer was washed with water (3×20 mL),followed by brine (25 mL), dried over anhydrous sodium sulfate andevaporated to afford crude material, which was purified by reverse phaseHPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 9.0 (s, 1H), 8.8 (d, 1H), 8.2(s, 1H), 8.0 (t, 2H), 7.3 (s, 1H), 4.8 (bs, 1H), 4.4 (bs, 1H), 3.9 (bs,1H), 3.6 (bs, 1H), 3.2 (bs, 2H), 3.18 (s, 3H), 2.8 (s, 3H), 2.5 (s, 3H),2.06 (s, 3H).

Example 77 Preparation of Compound No. 79

2-Allyl-8-methyl-5-(2-(pyridin-4-yl)vinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(50 mg, 0.151 mmol) was dissolved in DCM (2 mL), which was degassed withnitrogen for 15 min. To this was added Pd(PPh₃)₄ (4 mg, 0.002 mmol)followed by 1,3-dimethyl barbituric acid (71 mg, 0.454 mmol). Thereaction mixture was again degassed by nitrogen for 15 min. Theresultant mixture was stirred at RT for 1 h. DCM was evaporated invacuo. EtOAc (20 mL) was added to reaction mixture and was washed withsaturated potassium carbonate solution (3×1 mL). The organic layer wasdried over anhydrous sodium sulfate, evaporated in vacuo and purified byreverse phase HPLC to obtain 2 mg of8-methyl-5-(2-(pyridin-4-yl)vinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, Free base): δ (ppm): 8.45 (d, 2H), 8.0 (d, 1H), 7.7 (d,1H), 7.58 (d, 2H), 7.3 (s, 1H), 7.19 (d, 1H), 6.8 (d, 1H), 4.29 (s, 2H),3.42 (m, 2H), 3.2 (m, 2H), 2.4 (s, 3H).

Example 78 Preparation of Compound No. 80

To a degassed solution of trifluoro-methanesulfonic acid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-methyl-vinylester(200 mg, 0.515 mmol), potassium carbonate (214 mg, 1.550 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (150 mg,0.773 mmol) in DME:water (2:1 mL) was added Pd(PPh₃)₄ (30 mg, 0.025mmol) and the reaction mixture stirred at 90° C. for 1.5 h. The progressof reaction was monitored by TLC and LCMS. The reaction mixture wasdiluted with water (25 mL) and extracted with EtOAc (2×25 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentrated.The residue was purified by silica gel column chromatography followed byreverse phase HPLC to yield the desired product. ¹H NMR (CD₃OD, TFAsalt) δ (ppm): 7.3 (s, 1H), 7.08 (d, 1H), 7.0 (d, 1H), 6.92 (s, 2H), 6.5(s, 1H), 4.76 (d, 1H), 4.39 (d, 1H), 3.75 (m, 1H), 3.43 (m, 1H), 3.05(s, 3H), 2.9 (m, 2H), 2.41 (s, 3H), 2.25 (s, 3H).

Example 79 Preparation of Compound Nos. 81, 81a and 81b

To a solution of8-isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g,4.38 mmol) in DMF (20 mL) was added sodium hydride (526 mg, 13.14 mmol)and the suspension was stirred at RT for 10 min. A solution of4-(oxiran-2-yl)pyridine (1.0 g, 8.26 mmol) in DMF (5 mL) was addeddropwise, and stirring was continued overnight. The progress of reactionwas monitored by TLC and LCMS. The reaction mixture was poured into icecold water (200 mL) and extracted with EtOAc (3×200 mL). The organiclayer was washed with water (4×300 mL), dried over anhydrous sodiumsulfate and concentrated. The residue obtained was triturated withdiethyl ether (200 mL) to yield the desired product. ¹H NMR (CDCl₃,freebase) δ (ppm): 8.58 (d, 2H), 7.21 (d, 2H), 7.18 (d, 2H), 7.03 (d,1H), 4.81 (t, 1H), 4.05 (d, 2H), 3.55 (dd, 2H), 3.0 (q, 1H), 2.82 (m,1H), 2.7 (m, 2H), 2.6 (m, 1H), 2.4 (s, 3H), 1.3 (d, 6H). Separation bychiral HPLC provides enantiomers 81a and 81b.

Example 80 Preparation of Compound Nos. 82, 82a and 82b

To a solution of 2,6-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(1.0 g, 5.00 mmol) in DMF (10 mL) was added sodium hydride (600 mg, 15mmol) under nitrogen atmosphere at 0° C. and stirred for 10 min.4-(Oxiran-2-yl)pyridine (1.08 g, 8.92 mmol) was added dropwise undernitrogen atmosphere. The reaction mixture was stirred at RT for 12 h.The progress of reaction was monitored by TLC and LCMS. The reactionmixture was poured in ice-cold water and extracted with EtOAc (2×100mL). The combined organic layer was washed with water (5×50 mL), driedover anhydrous sodium sulfate and concentrated. The residue wascrystallized with diethyl ether to yield2-(2,6-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.58 (d, 2H), 7.23 (m, 3H), 7.0 (t,1H), 6.9 (d, 1H), 4.81 (t, 1H), 4.3-4.4 (m, 2H), 3.5 (dd, 2H), 3.0 (m,1H), 2.8 (m, 1H), 2.75 (s, 3H), 2.7 (m, 1H), 2.6 (m, 1H), 2.43 (s, 3H).Separation by chiral HPLC provides enantiomers 82a and 82b.

Example 81 Preparation of Compound No. 83

2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 10 mmol)was dissolved in mL of DMF. The resulting solution was cooled in anice-water bath and sodium hydride (840 mg, 4.2 mmol) was added undernitrogen atmosphere. 2-Bromomethyl-2-phenyl[1,3]dioxolane (2.43 g, 10mmol) was added and the reaction mixture was heated at 100° C.overnight. Water was added and the product was extracted with EtOAc. Theorganic layer was washed with water, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel chromatography eluting with 0-5% MeOH:DCM.

Example 82

Compound Nos. 84, 85, 86, 89, 90, 90a, 90b and 91 were synthesized asdescribed in PCT publication WO-2009/055828; see, for example, syntheticprocedures 20, 23, 87, 178 and 274.

Example 83

Compound Nos. 87 and 88 were synthesized as described in PCT publicationWO-2009/094668; see, for example, synthetic procedures 71 and 72.

Example 84

Compound Nos. 95,95a-b, 97 and 97a-b were synthesized as described inPCT publication WO-2009/120720; see, for example, synthetic procedures109 and 115.

Example 85

Compound Nos. 96 and 96a-b were synthesized as described in PCTpublication WO-2009/120717; see, for example, synthetic procedure 131.

Example 86

Compound Nos. 93,93a-b, 98,98a-b, 100, 101, 103, 105, 107 and 132 weresynthesized as described in PCT publication WO-2010/051501; see, forexample, synthetic procedures 45, 131, 199, 241, 273, 329, 341, 354 and401.

Example 87

Compound Nos. 92, 99 and 106 were synthesized as described in PCTpublication WO-2010/051503; see, for example, synthetic procedures 41,147 and 168.

Example 88

Compound No. 94 was synthesized as described in PCT publicationWO-2010/127177; see, for example, synthetic procedure 6.

Example 89

Compound Nos. 102 and 102a-b were synthesized as described in PCTpublication WO-2011/019417; see, for example, synthetic procedure 9.

Example 90 Preparation of Compound No. 108

To a degassed solution of[(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate] (50 mg, 0.128 mmol), potassium carbonate(17.8 mg, 0.1287 mmol) and 1-methyl-1H-pyrazole-5-boronic acid pinacolester (53.5 mg, 0.2574 mmol) in DME-water (2 mL: 1 mL) was addedPd(PPh₃)₄ (7.4 mg, 0.0064) and the reaction mixture was heated to refluxfor 2.5 h. The reaction mixture was cooled to RT and the solvent wasremoved under reduced pressure. The residue was diluted with water andextracted with EtOAc. The organic layer was washed with brine, andconcentrated under reduced pressure. The residue was purified by reversephase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.58 (d, 1H), 7.26 (d,1H), 7.18 (m, 2H), 6.93 (s, 1H), 6.45 (s, 1H), 4.78 (d, 1H), 4.39 (d,1H), 4.02 (s, 3H), 3.86 (m, 1H), 3.59 (m, 1H), 3.23 (m, 1H), 3.18 (m,4H), 2.42 (s, 3H), 1.87 (s, 3H).

Example 91 Preparation of Compound No. 109

To a degassed solution of[(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate] (100 mg, 0.257 mmol),1-methylpyrazole-4-boronic acid pinacol ester (108 mg, 0.515 mmol) andpotassium carbonate (36 mg, 0.257 mmol) in DME-water (4:2 mL) was addedPd(PPh₃)₄ (15 mg, 0.0128) and the reaction mixture was heated to refluxfor 45 min. The reaction mixture was cooled to RT, and the solvent wasremoved under reduced pressure. The residue was diluted with water andextracted with EtOAc. The organic layer was washed with brine, andconcentrated under reduced pressure. The residue was purified by reversephase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.92 (s, 1H), 7.89 (s,1H), 7.26 (s, 1H), 7.16 (m, 2H), 6.98 (s, 1H), 4.78 (d, 1H), 4.37 (d,1H), 3.85 (s, 3H), 3.82 (m, 1H), 3.58 (m, 1H), 3.18 (s, 3H), 3.13 (m,2H), 2.43 (s, 3H), 1.82 (s, 3H).

Example 92 Preparation of Compound No. 110

To a degassed solution of[(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate] (100 mg, 0.257 mmol),3,5-dimethylisoxazole-4-boronic acid pinacol ester (115 mg, 0.515 mmol)and potassium carbonate (36 mg, 0.257 mmol) in DME-water (4:2 mL) wasadded Pd(PPh₃)₄ (15 mg, 0.0128) and the reaction mixture was heated toreflux for 45 min. The reaction mixture was cooled to RT, and thesolvent was removed under reduced pressure. The residue was diluted withwater and extracted with EtOAc. The organic layer was washed with brine,and concentrated under reduced pressure. The residue was purified byreverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.27 (s, 1H), 7.17(m, 2H), 6.61 (s, 1H), 4.78 (d, 1H), 4.39 (d, 1H), 3.83 (m, 1H), 3.60(m, 1H), 3.02-3.23 (m, 5H), 2.31-2.60 (m, 9H), 1.81 (s, 3H).

Example 93 Preparation of Compound No. 111

To a solution of[(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate] (100 mg), potassium carbonate (36 mg), and2-acetamidopyridine-5-boronic acid pinacol ester (135 mg) in DME-water(4:2 mL) was added Pd(PPh₃)₄ (15 mg) and the reaction mixture was heatedto reflux for 45 min. The reaction mixture was cooled to RT, and thesolvent was removed under reduced pressure. The residue was diluted withwater and extracted with EtOAc. The organic layer was washed with brine,and concentrated under reduced pressure. The residue was purified byreverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.91 (s, 1H), 7.68(d, 1H), 7.58 (d, 1H), 7.21 (s, 1H), 7.10 (d, 1H), 6.98 (d, 1H), 6.91(s, 1H), 4.61 (d, 1H), 4.30 (d, 1H), 3.71 (m, 1H), 3.40 (m, 1H), 3.07(s, 3H), 2.90 (m, 2H), 2.38 (m, 6H), 2.16 (s, 3H).

Example 94 Preparation of Compound No. 112

To a solution of[(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate] (100 mg), potassium carbonate (36 mg), and2-acetamidopyridine-5-boronic acid pinacol ester (135 mg) in DME-water(4:2 mL) was added Pd(PPh₃)₄ (15 mg) and the reaction mixture was heatedto reflux for 45 min. The reaction mixture was cooled to RT, and thesolvent was removed under reduced pressure. The residue was diluted withwater and extracted with EtOAc. The organic layer was washed with brine,and concentrated under reduced pressure. The residue was purified byreverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.58 (s, 1H), 8.35(d, 1H), 7.96 (d, 1H), 7.30 (s, 1H), 7.11 (m, 3H), 4.37 (d, 1H), 4.40(d, 1H), 3.83 (m, 1H), 3.58 (m, 1H), 3.12 (m, 5H), 2.42 (s, 3H), 2.21(s, 3H), 2.0 (s, 3H).

Example 95 Preparation of Compound No. 113

To a degassed solution of[(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate] (100 mg, 0.257 mmol), potassium carbonate (36mg, 0.257 mmol) and naphthalene-1-boronic acid (88 mg, 0.515 mmol) inDME-water (4:2 mL) was added Pd(PPh₃)₄ (15 mg, 0.0128 mmol) and thereaction mixture was heated to reflux for 45 min. The reaction mixturewas cooled to RT, and the solvent was removed under reduced pressure.The residue was diluted with water and extracted with EtOAc. The organiclayer was washed with brine and concentrated under reduced pressure. Theresidue was purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 8.18 (d, 1H), 7.84-7.98 (m, 2H), 7.51-7.62 (m, 4H), 7.38 (m, 2H),7.18 (d, 1H), 6.78 (s, 1H), 4.67 (m, 1H), 4.42 (m, 1H), 3.81 (m, 1H),3.63 (m, 1H), 3.24 (m, 1H), 3.21 (s, 3H), 3.19 (m, 1H), 2.47 (s, 3H),2.12 (s, 3H).

Example 96 Preparation of Compound No. 114

To a degassed solution of5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(120 mg, 0.348 mmol), 4-pyridineboronic acid (85 mg, 0.69 mmol) andpotassium carbonate (144 mg, 1.04 mmol) in DME-water (4:2 mL) was addedPd(PPh₃)₄ (20 mg, 0.0174 mmol) and the reaction mixture was heated toreflux for 45 min. The reaction mixture was cooled to RT, and thesolvent was removed under reduced pressure. The residue was diluted withwater and extracted with EtOAc. The organic layer was washed with brineand concentrated under reduced pressure. The residue was purified byreverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.52 (d, 2H), 7.40(m, 2H), 7.36 (s, 1H), 6.92-7.15 (m, 2H), 4.78 (d, 1H), 4.40 (d, 1H),3.80 (m, 1H), 3.51 (m, 1H), 3.20 (m, 6H), 2.80-3.00 (m, 3H), 2.41 (s,3H), 2.37 (m, 2H).

Example 97 Preparation of Compound No. 115

To a degassed solution of(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg, 0.257 mmol), potassium carbonate (110mg, 0.77 mmol) and 1H-pyrazole-4-boronic acid (60 mg, 0.540 mmol) inDME-water (2:1 mL) was added Pd(PPh₃)₄ (20 mg, 0.017 mmol) and thereaction mixture was heated to reflux for 45 min. The reaction mixturewas cooled to RT, and the solvent was removed under reduced pressure.The residue was diluted with water and extracted with EtOAc. The organiclayer was washed with brine and concentrated under reduced pressure. Theresidue was purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 8.0 (s, 2H), 7.27 (s, 1H), 7.0-7.11 (m, 3H), 4.7 (d, 1H), 4.37(d, 1H), 3.82 (m, 1H), 3.56 (m, 1H), 3.01-3.22 (m, 5H), 2.41 (s, 3H),1.80 (s, 3H).

Example 98 Preparation of Compound No. 116

To a de-aerated solution of8-chloro-5-(2-chloroallyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(200 mg, 0.680 mmol) and potassium carbonate (281 mg, 2.039 mmol) in1,2-dimethoxyethane-water (2:1) were added pyridine-4-boronic acid(167.2 mg, 1.36 mmol) and Pd(PPh₃)₄ (53 mg, 0.045 mmol). The reactionmixture was stirred at 90° C. for 45 min. The reaction mixture wasconcentrated under reduced pressure to dryness. The residue obtained wasdissolved in EtOAc (50 mL) and washed with water (20 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure to afford crude product, which was purified by reversephase HPLC. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.6 (d, 2H), 7.4 (s, 1H),7.3 (d, 2H), 7.1 (s, 2H), 5.57 (s, 1H), 4.98 (s, 2H), 4.58 (s, 1H), 3.82(s, 2H), 3.05 (t, 2H), 2.82 (t, 2H), 2.6 (s, 3H).

Example 99 Preparation of Compound No. 117

To a degassed solution of5-(5-fluoro-pyridin-3-ylethynyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(60 mg, 0.188 mmol) in MeOH (3 mL) were added 10% dry Pd—C (35 mg) andammonium formate (59 mg, 0.940 mmol). The reaction mixture was stirredat 75° C. for 1 h. The reaction mass was filtered through Celite and thefiltrate concentrated under reduced pressure to afford crude product,which was purified by reverse phase HPLC to yield5-[2-(5-fluoro-pyridin-3-yl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.3 (s, 1H), 7.9 (s, 1H), 7.38 (d,1H), 7.21 (s, 1H), 7.2 (d, 1H), 7.0 (d, 1H), 4.62 (d, 1H), 4.4 (t, 2H),4.3 (d, 1H), 3.78 (m, 1H), 3.4 (m, 1H), 3.18 (t, 2H), 3.1 (s, 3H), 2.9(m, 1H), 2.8 (m, 1H), 2.4 (s, 3H).

Example 100 Preparation of Compound No. 118

A mixture of5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300mg, 1.33 mmol), 1H-imidazole (182 mg, 2.66 mmol), TBAF.3H₂O (1.2 g, 3.80mmol) and dichloro bis(triphenylphosphine) palladium (II) (47 mg, 0.06mmol) was heated at 85° C. for 30 min. The reaction mixture was cooledto RT, diluted with water and extracted with EtOAc (3×25 mL). Theorganic layer was washed with water (3×25 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (100-200 mesh) eluting with 4%MeOH-DCM to yield 90 mg of5-(1-imidazol-1-yl-vinyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.The free base was converted into the di-HCl salt by treatment withethanolic HCl. ¹H NMR (CD₃OD, Di-HCl salt) δ (ppm): 9.21 (s, 1H), 7.78(d, 2H), 7.38 (s, 1H), 7.1 (d, 1H), 6.92 (d, 1H), 6.21 (d, 1H), 5.75 (d,1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.83 (m, 1H), 3.6 (m, 1H), 3.18 (m, 5H),2.4 (s, 3H).

Example 101 Preparation of Compound No. 119

To a solution of2-methyl-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.393 mmol) in DMF (2 mL) were added sodium hydride (60 mg,1.17 mmol) and 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate(300 mg, 0.98 mmol). The reaction mixture was irradiated in a microwavereactor at 90° C. for 1 h. The reaction mixture was cooled to RT andquenched with water and extracted with EtOAc (3×10 mL). The organiclayer was washed with water (10 mL×2), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford crude product,which was purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 8.21 (s, 1H), 8.07 (d, 1H), 7.6 (dd, 2H), 7.28 (m, 2H), 4.78 (d,1H), 4.6 (t, 2H), 4.4 (d, 1H), 3.9 (m, 1H), 3.6 (m, 1H), 3.2-3.4 (m,4H), 3.18 (s, 3H), 2.6 (s, 3H).

Example 102 Preparation of Compound No. 120

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(200 mg, 1.00 mmol) and 2-aminopyridine (188 mg, 2.00 mmol) in DCM (2mL) was added powdered KOH (392 mg, 7.00 mmol), and the reaction mixturewas stirred at 85° C. for 2 h. The progress of reaction was monitored byTLC and LCMS. DCM was removed under reduced pressure. Water was added tothe residue and extracted with EtOAc (2×50 mL). The organic layer wasdried over anhydrous sodium sulfate and concentrated to afford crudematerial, which was purified by reverse phase HPLC to yield(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-ylmethyl)-pyridin-2-yl-amine.¹H NMR (CDCl₃, freebase) δ (ppm): 8.1 (d, 1H), 7.38 (m, 2H), 7.18 (s,1H), 7.0 (d, 1H), 6.6 (t, 1H), 6.3 (d, 1H), 5.57 (s, 2H), 5.26 (bs, 1H),3.8 (s, 2H), 3.1 (t, 2H), 3.0 (t, 2H), 2.6 (s, 3H), 2.4 (s, 3H).

Example 103 Preparation of Compound No. 121

To a de-aerated solution of5-(2-chloroallyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(150 mg, 0.547 mmol) and potassium carbonate (226 mg, 1.64 mmol) in1,2-dimethoxyethane-water (2:1) were added pyridine-4-boronic acid (135mg, 1.09 mmol) and Pd(PPh₃)₄ (44 mg, 0.0383 mmol). The reaction mixturewas stirred at 90° C. for 45 min. The reaction mixture was cooled to RTand concentrated under reduced pressure to dryness. The residue obtainedwas dissolved in EtOAc (50 mL) and washed with water (20 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford crude product, which was purified byreverse phase HPLC as a TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.8(d, 2H), 8.2 (d, 2H), 7.3 (m, 2H), 7.05 (d, 1H), 6.0 (s, 1H), 5.3 (d,2H), 4.8 (s, 1H), 4.7 (d, 1H), 4.37 (d, 1H), 3.86 (m, 1H), 3.6 (m, 1H),3.17 (m, 2H), 3.1 (s, 3H), 2.43 (s, 3H).

Example 104 Preparation of Compound No. 122

To a degassed solution of(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg, 0.257 mmol) and potassium carbonate(110 mg, 0.796 mmol), in DME (2 mL) and water (1 mL) were addedPd(PPh₃)₄ (20 mg, 0.017 mmol) andN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide(135 mg, 0.514 mmol) and the reaction mixture was heated to reflux for45 min. The reaction mixture was cooled to RT, and the solvent wasremoved under reduced pressure. The residue was diluted with water andextracted with EtOAc. The organic layer was washed with brine andconcentrated under reduced pressure. The residue was purified by reversephase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.9 (s, 1H), 8.1-8.21 (m,2H), 7.3 (s, 1H), 7.19 (s, 1H), 7.1 (m, 2H), 4.76 (d, 1H), 4.4 (d, 1H),3.82 (bs, 1H), 3.6 (bs, 1H), 3.2 (m, 2H), 3.17 (s, 3H), 3.0 (s, 3H),2.42 (s, 3H), 2.0 (s, 3H).

Example 105 Preparation of Compound No. 124

To a degassed solution of3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene (201 mg, 1.00mmol), potassium phosphate (466 mg, 2.20 mmol), L-proline (19 mg, 0.10mmol) and copper iodide (23 mg, 0.20 mmol) in DMF (2 mL) was added4-(2-bromo-1-methyl-vinyl)-pyridine (396 mg, 2.00 mmol). The reactionmixture was stirred at 120° C. for 16 h. The progress of reaction wasmonitored by TLC and LCMS. The reaction mixture was diluted with water(20 mL) and extracted with EtOAc (3×10 mL). The organic layer was washedwith water (3×20 mL), followed by brine (25 mL), dried over anhydroussodium sulfate and evaporated to afford crude material, which waspurified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.8(bs, 2H), 8.22 (d, 2H), 8.18 (s, 1H), 7.8 (s, 1H), 7.6 (s, 1H), 4.76(bs, 1H), 4.4 (bs, 1H), 3.82 (bs, 1H), 3.6 (bs, 1H), 3.21 (bs, 2H), 3.1(s, 3H), 2.42 (s, 3H), 2.1 (s, 3H).

Example 106 Preparation of Compound No. 125

To a stirred solution of(E)-5-(2-(6-(methoxymethyl)pyridin-3-yl)prop-1-en-1-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(90 mg, 0.249 mmol) in dry DCM (3 mL) was dropwise addition of solutionof BBr₃ (0.3 mL, 1.745 mmol) in dry DCM (2 mL) at −78° C. and thereaction mixture was stirred at −78° C. for 2 h. The solvent was removedunder reduced pressure. The residue was basified with saturated sodiumbicarbonate solution and extracted with DCM (3×20 mL). The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford crude product, which was purified by reverse phaseHPLC to yield(E)-(5-(1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yl)pyridin-2-yl)methanolas the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.9 (s, 1H), 8.77 (d,1H), 8.0 (d, 1H), 7.4 (s, 1H), 7.3 (s, 1H), 7.17 (d, 1H), 7.1 (d, 1H),5.1 (d, 1H), 5.0 (s, 2H), 4.6 (d, 1H), 4.1 (m, 2H), 3.17 (s, 3H), 3.1(bs, 2H), 2.42 (s, 3H), 2.1 (s, 3H).

Example 107 Preparation of Compound No. 126

To a degassed solution of(Z)-2,8-dimethyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-1-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3b]indole(271 mg, 0.742 mmol), 5-bromo-2-(methoxymethyl)pyridine (100 mg, 0.495)and potassium carbonate (204 mg, 1.485 mmol) in DME-water (2:1 mL) andwas added Pd(PPh₃)₄ (40.0 mg, 0.034 mmol), and the reaction mixture washeated to reflux for 45 min. The reaction mixture was cooled to RT, andthe solvent was removed under reduced pressure. The residue was dilutedwith water and extracted with EtOAc. The organic layer was washed withbrine and concentrated under reduced pressure. The residue was purifiedby reverse phase HPLC. ¹H NMR (CD₃OD, Di-HCl salt) δ (ppm): 9.0 (s, 1H),8.84 (d, 1H), 8.05 (d, 1H), 7.42 (s, 1H), 7.3 (s, 1H), 7.15 (d, 1H), 7.1(d, 1H), 4.9 (s, 2H), 4.78 (d, 1H), 4.4 (d, 1H), 3.82 (bs, 1H), 3.6 (s,3H), 3.58 (bs, 1H), 3.2 (bs, 2H), 3.1 (s, 3H), 2.43 (s, 3H), 2.1 (s,3H).

Example 108 Preparation of Compound Nos. 127 and 127a-d

To an ice-cooled stirred suspension of 4-bromopyridine hydrochloridesalt (1.0 g, 5.1 mmol) in THF (5 mL) was added isopropyl magnesiumchloride (2M in THF, 5 mL, 10.3 mmol) and stirred the reaction at RT for30 min. A solution of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanal (300mg, 1.17 mmol) in THF (3 mL) was added into the brown colored reactionmixture, which was stirred at RT for 1.5 h. The progress of reaction wasmonitored by TLC and LCMS (45% conversion). The reaction mixture wascooled to 0° C. and quenched with cold saturated ammonium chloridesolution (till effervescence stops) and added water, stirred at RT for15 min and extracted with EtOAc. The organic layer was dried overanhydrous sodium sulfate and evaporated. The residue was purified byreverse phase HPLC. The product was further purified, and enantiomersseparated, by chiral preparative HPLC. ¹H NMR (CDCl₃, freebase) δ (ppm):8.20 (d, 2H), 7.1 (s, 1H), 7.06 (s, 1H), 6.86 (d, 1H), 6.8 (s, 2H), 4.85(s, 1H), 4.2 (s, 1H), 3.49 (d, 1H), 3.39 (d, 1H), 2.61 (d, 2H), 2.41 (s,3H), 2.33 (s, 3H), 1.56 (s, 3H). Separation by chiral HPLC provideddiastereomers 127a-d.

Example 109 Preparation of Compound Nos. 128 and 128a-b

A solution of tert-butyl9-(2-hydroxy-2-(pyridin-3-yl)propyl)-6-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate(350 mg) in 3M aqueous HCl solution (10 mL) was stirred at RT for 1 h.The progress of reaction was monitored with TLC and LCMS. The reactionmixture was lyophilized and the solid obtained was washed with diethylether (2×30 mL), dried to yield the title compound. The product wasfurther purified, and enantiomers separated, by chiral preparative HPLC.¹H NMR (CD₃OD, HCl salt) δ (ppm): 8.67 (d, 1H), 8.6 (d, 1H), 8.54 (s,1H), 7.9 (t, 1H), 7.2 (s, 1H), 6.8 (d, 1H), 6.7 (s, 1H), 4.98 (d, 1H),4.6 (d, 1H), 4.4 (q, 2H), 3.62 (t, 2H), 3.07 (m, 2H), 2.32 (s. 3H), 1.8(s, 3H). Separation by chiral HPLC provided enantiomers 128a and 128b.

Example 110 Preparation of Compound Nos. 129 and 129a-d

To a solution of9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene(100 mg, 0.442 mmol) in DMF (2 mL) was added sodium hydride (60%, 53 mg,1.32 mmol) at 0° C. After stirring for 5 min, 4-oxiranyl-pyridine (81mg, 0.669 mmol) was added at 0° C. and the mixture stirred at RT for 12h. The progress of reaction was monitored by TLC and LCMS. The reactionmixture was poured into ice-cold water and extracted with EtOAc (2×25mL). The combined organic layer was washed with water (5×25 mL), driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by reverse phase HPLC to Compound No. 129 (90mg), which was separated by chiral prep HPLC to give compounds 129a,129b, 129c and 129d. Compound No. 129a: ¹HNMR (CDCl₃, freebase) δ (ppm):8.58 (d, 2H), 7.25 (m, 4H), 7.04 (d, 1H), 5.08 (t, 1H), 4.3 (bs, 1H),4.18 (d, 2H), 3.3 (d, 1H), 3.07 (m, 2H), 2.85 (m, 2H), 2.6 (m, 1H), 2.42(m, 1H), 2.4 (s, 3H), 2.01 (m, 3H), 1.82 (m, 1H). Compound No. 129b:¹HNMR (CDCl₃, freebase) δ (ppm): 8.55 (d, 2H), 7.25 (m, 4H), 7.0 (d,1H), 5.0 (t, 1H), 4.3 (bs, 1H), 4.19 (m, 2H), 3.32 (d, 1H), 3.0 (m, 4H),2.5 (m, 2H), 2.45 (s, 3H), 2.0 (m, 2H), 1.9 (m, 1H). Compound No. 129c:¹HNMR (CDCl₃, freebase) δ (ppm): 8.6 (d, 2H), 7.25 (m, 4H), 7.0 (d, 1H),5.05 (t, 1H), 4.2 (m, 2H), 3.9 (t, 1H), 3.3 (m, 1H), 2.91 (m, 2H), 2.8(t, 1H), 2.7 (q, 1H), 2.43 (s, 3H), 2.4 (m, 2H), 1.9 (m, 3H). CompoundNo. 129d: ¹HNMR (CDCl₃, freebase) δ (ppm): 8.58 (d, 2H), 7.25 (m, 4H),7.04 (d, 1H), 5.08 (t, 1H), 4.3 (bs, 1H), 4.18 (d, 2H), 3.3 (d, 1H),3.07 (m, 2H), 2.85 (m, 2H), 2.6 (m, 1H), 2.42 (m, 1H), 2.4 (s, 3H), 2.01(m, 3H), 1.82 (m, 1H).

Example 111 Preparation of Compound Nos. 130 and 130a-b

To an ice-cooled stirred solution of2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol(50 g, 155.76 mmol) in DMF (300 mL) was added NaH (60%, 12.5 g, 312.5mmol). After stirring at RT for 15 min, pivaloyl chloride (37.38 g,311.5 mmol) was added dropwise into the reaction mixture, which wasstirred at RT for 1 h. The reaction was quenched with EtOH and dilutedwith ice water. The product was extracted with EtOAc, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was passed through a silica gel filter column to remove excesspivaloyl chloride and yield title compound as yellow solid (22.3 g). Theproduct was further purified by chiral preparative HPLC. ¹H NMR (CDCl₃,freebase) δ (ppm): 8.54 (d, 2H), 7.21 (d, 1H), 7.2 (s, 1H), 7.0 (d, 2H),6.95 (d, 1H), 6.0 (t, 1H), 4.4 (dd, 1H), 4.1 (dd, 1H), 3.62 (q, 2H), 2.7(m, 3H), 2.52 (s, 3H), 2.41 (s, 3H), 2.3 (m, 1H), 1.19 (s, 9H).

Example 112 Preparation of Compound Nos. 131 and 131a-b

To solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(160 mg, 0.8 mmol) in DMF (3 mL) was added NaH (60%, 96 mg, 2.4 mmol).After stirring for 5 min at RT, 1-methyl-4-(oxiran-2-yl)-1H-pyrazole(150 mg, 1.2 mmol) was added into the reaction mixture, which wasstirred at RT for 26 h. The progress of reaction was monitored by TLC,NMR and LCMS. The reaction mixture was quenched with ice-water andextracted with EtOAc. The organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography (EtOH-Hex) to yield2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(1-methyl-1H-pyrazol-4-yl)ethanol.The product was further purified by chiral HPLC separation. ¹H NMR(CDCl₃, freebase) δ (ppm): 7.46 (s, 1H), 7.2 (s, 1H), 7.19 (s, 1H), 7.15(d, 1H), 6.98 (d, 1H), 5.0 (t, 1H), 4.2 (d, 2H), 3.82 (s, 3H), 3.6 (s,2H), 2.9 (m, 1H), 2.8 (m, 2H), 2.7 (m, 1H), 2.5 (s. 3H), 2.42 (s, 3H).

Example 113 Preparation of Compound Nos. 133 and 133a-b

To a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(100 mg, 0.5 mmol) in DMF (2 mL) was added NaH (60 mg, 1.5 mmol). Afterstirring for 10 min at RT, a solution of3-methyl-4-(oxiran-2-yl)pyridine (100 mg, 0.75 mmol) in DMF (1 mL) wasadded into the reaction mixture, which was stirred at RT for 16 h. Theprogress of reaction was monitored by TLC, LCMS and NMR. The reactionmixture was quenched with ice-water and extracted with EtOAc. Theorganic layer was washed with water, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified byreverse phase HPLC. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.42 (d, 1H), 8.30(s, 1H), 7.50 (d, 1H), 7.10 (m, 2H), 6.95 (d, 1H), 5.10 (m, 1H), 4.05(m, 2H), 3.50 (s, 2H), 2.95-2.60 (m, 4H), 2.42 (s, 6H), 2.20 (s, 3H).Separation by chiral HPLC provided enantiomers 133a and 133b.

Example 114 Preparation of Compound Nos. 134 and 134a-b

A mixture of9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene(100 mg, 0.44 mmol), 3-vinyl-pyridine (185 mg, 1.762 mmol),tetrabutylammonium bromide (425 mg, 1.32 mmol) and 50% NaOH solution (6mL) was stirred at 100° C. for 18 h. The progress of reaction wasmonitored by TLC and LCMS. The reaction mixture was diluted with water(20 mL) and extracted with EtOAc (2×50 mL). The combined organic layerwas washed with brine solution (50 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to yield9-methyl-6-(2-pyridin-3-yl-ethyl)-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene(58 mg). ¹H NMR (CDCl₃, freebase) δ (ppm): 8.41 (d, 1H), 8.27 (s, 1H),8.07 (s, 1H), 7.58 (s, 1H), 7.2 (d, 1H), 7.1 (dd, 1H), 4.4 (m, 2H), 3.99(bs, 1H), 3.2 (dd, 1H), 3.17 (t, 2H), 2.84-2.7 (m, 3H), 2.5 (m, 1H),2.41 (s, 3H), 2.2 (dd, 1H), 1.9 (m, 4H). Separation by chiral HPLCprovided enantiomers 134a and 134b.

Example 115 Preparation of Compound Nos. 135 and 135a-b

To a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(400 mg, 1.61 mmol) in DMF (5 mL) was added NaH (240 mg, 6.0 mmol).After stirring at RT for 15 min, 3-chloro-4-(oxiran-2-yl)pyridine (620mg, 4.0 mmol) was added into the reaction mixture, which was stirred atRT for 8 h. The progress of reaction was monitored by TLC and LCMS. Thereaction mixture was quenched with ice-water and extracted with EtOAc(3×50 mL). The organic layer was washed with water (5×50 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theproduct was crystallized from ether to yield title compound (430 mg)which was separated by chiral preparative HPLC to obtain 135a and 135b.¹H NMR (CDCl₃, freebase) δ (ppm): 8.4 (s, 1H), 8.21 (d, 1H), 7.39 (d,1H), 7.1 (d, 1H), 6.97 (s, 1H), 6.88 (d, 1H), 5.7 (bs, 1H), 5.19 (d,1H), 4.21 (d, 1H), 3.89 (dd, 1H), 3.23 (dd, 2H), 2.86 (m, 2H), 2.67 (m,2H), 2.45 (s, 3H), 2.29 (s, 3H).

Example 116 Preparation of Compound Nos. 136 and 136a-b

To a solution of aza carboline (500 mg, 2.48 mmol) in DMF (5 mL) wasadded NaH (298 mg, 7.46 mmol). After stirring at RT for 10 min,2-(4-fluorophenyl)oxirane (515 mg, 3.73 mmol) was added into thereaction mixture, which was stirred at RT for 16 h. The progress ofreaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice water and extracted with EtOAc. The organic layer waswashed thoroughly with water, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The product was recrystallized fromether and further separated by chiral preparative HPLC to obtain 136aand 136b. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.02 (s, 1H), 7.5 (s, 1H),7.23 (m, 2H), 7.0 (t, 2H), 6.6 (bs, 1H), 5.11 (d, 1H), 4.3 (d, 1H), 4.24(dd, 1H), 3.56 (dd, 2H), 2.74 (m, 2H), 2.6 (m, 1H), 2.49 (s, 3H), 2.44(m, 1H), 2.41 (s, 3H).

Example 117 Preparation of Compound Nos. 137 and 137a-b

To a solution of9-chloro-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene(400 mg, 1.61 mmol) in DMF (5 mL) was added sodium hydride (195 mg, 4.87mmol). After stirring for 10 min at RT, 2-(6-methylpyridin-3-yl)ethyl4-methylbenzenesulfonate (1.08 g, 3.71 mmol) was added into the reactionmixture, which was stirred at RT for 1 h. The progress of reaction wasmonitored by TLC and LCMS. The reaction mixture was quenched withice-water and extracted with EtOAc. The organic layer was washed withwater, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography followed by reverse phase HPLC to yield the titlecompound. Separation by chiral HPLC provided enantiomers 133a and 133b.¹H NMR (CDCl₃, freebase) δ (ppm): 8.2 (s, 1H), 8.19 (s, 1H), 7.7 (s,1H), 7.1 (d, 1H), 7.0 (d, 1H), 4.38 (m, 2H), 3.8 (bs, 1H), 3.03 (t, 2H),2.8 (m, 2H), 2.7 (m, 1H), 2.4 (m, 1H), 2.5 (s, 3H), 2.38 (m, 1H), 2.12(dd, 1H), 1.8 (m, 4H). Separation by chiral HPLC provided enantiomers137a and 137b.

Example 118 Preparation of Compound Nos. 138 and 138a-b

To a solution of dimethyl-aza carboline (693 mg, 3.4 mmol) in DMF (5 mL)was added NaH (413 mg, 10.3 mmol, 60%). After stirring at RT for 10 min,2-(4-fluorophenyl)-2-methyloxirane (1.0 g, 6.8 mmol) was added into thereaction mixture, which was stirred at RT for 16 h. The progress ofreaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice-water and extracted with EtOAc. The organic layer waswashed with water, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified through reverse phaseHPLC to obtain the racemate which was separated by chiral preparativeHPLC to obtain 138a and 138b. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.01 (s,1H), 7.49 (s, 1H), 7.24 (m, 2H), 6.95 (t, 2H), 4.27 (dd, 2H), 3.62 (d,1H), 3.5 (d, 1H), 2.8 (m, 3H), 2.49 (s, 3H), 2.45 (m, 1H), 2.4 (s, 3H),1.53 (s, 3H).

Example 119 Preparation of Compound Nos. 139 and 139a-b

A solution of4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzoicacidethyl ester (90 mg, 0.229 mmol) in 25% ammonium hydroxide solution (5mL) was stirred at 120° C. for 1 h. The progress of reaction wasmonitored by NMR and LCMS. The reaction mixture was cooled to RT,diluted with water and extracted with EtOAc (3×30 mL). The combinedorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by reverse phase HPLCto yield4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzamide(3 mg) which was separated by chiral preparative HPLC to obtain 139a and139b. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.18 (t, 2H), 7.4 (d, 1H), 7.31(d, 2H), 7.23 (s, 1H), 7.03 (t, 1H), 5.08 (t, 1H), 4.64 (dd, 1H), 4.33(m, 2H), 4.21 (dd, 1H), 3.71 (t, 1H), 3.45 (bs, 1H), 3.12 (m, 1H), 3.09(d, 3H), 2.6 (d, 1H), 2.41 (s, 3H).

Example 120 Preparation of Compound Nos. 140 and 140a-b

To a degassed solution of1-(6-bromo-pyridin-3-yl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanol(1 g, 2.5 mmol) in DMF (10 mL) were added Pd(PPh₃)₄ (0.173 g, 0.15 mmol)and zinc cyanide (585 mg, 5.0 mmol) and the reaction mixture was stirredat 150° C. for 2 h. The reaction mixture was cooled to RT, diluted withEtOAc (250 mL) and filtered. The filtrate was washed with water (3×100mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated. The residue was purified by reverse phase HPLC to yield5-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile(350 mg). ¹H NMR (CDCl₃, freebase) δ (ppm): 8.55 (s, 1H), 7.38 (d, 1H),7.23 (d, 1H), 6.93 (s, 1H), 6.81 (s 1H), 6.74 (s, 1H), 4.96 (m, 1H),4.11 (dd, 2H), 3.29 (dd, 2H), 2.95 (m, 1H), 2.88 (m 1H), 2.86 (m, 2H),2.5 (s, 6H). Separation by chiral HPLC provided enantiomers 140a and140b.

Example 121 Preparation of Compound Nos. 141 and 141a-b

To a solution of2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol(2.0 g, 9.04 mmol) in DMF (20 mL) was added sodium hydride (1.0 g, 25mmol). After stirring at RT for 20 min, a solution of N,N-dimethylcarbamoyl chloride (1.9 g, 17.7 mmol) in DMF (5 mL) was added dropwiseinto the reaction mixture, which was stirred at RT for 1 h. The progressof reaction was monitored by TLC and LCMS. The reaction mixture waspoured into ice water (400 mL) and extracted with EtOAc (3×200 mL). Theorganic layer was washed with water (3×300 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (5-7% MeOH in DCM) to yieldN,N-dimethyl-carbamic acid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (100 mg). ¹H NMR (CD₃OD, freebase) δ (ppm): 8.5 (d, 2H), 7.34 (d,2H), 7.31 (d, 1H), 7.21 (s, 1H), 7.00 (d, 1H), 5.96 (t, 1H), 4.53 (dd,1H), 4.45 (dd, 1H), 3.49 (t, 2H), 2.98 (m, 2H), 2.95 (m, 5H), 2.92 (s,3H), 2.77 (s, 3H), 2.39 (s, 3H). Separation by chiral HPLC providedenantiomers 141a and 141b.

Example 122 Preparation of Compound Nos. 142 and 142a-b

To an ice-cooled stirred solution of2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (2.6 g, 13.24mmol) in DMF (12 mL) was added sodium hydride (1.6 g, 39.72 mmol, 60%).After stirring at 0° C. for 10 min, 4-(oxiran-2-yl)benzonitrile (2.4 g,16.55 mmol) was added into the reaction mixture, which was stirred at RTfor 16 h. The progress of reaction was monitored by TLC and LCMS. Thereaction mixture was quenched with ice-water and extracted with EtOAc.The organic layer was washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The product wasre-crystallized from ether (2.5 g) followed by chiral separation. ¹H NMR(CDCl₃, freebase) δ (ppm): 7.55 (d, 2H), 1.76 (d, 2H), 7.11 (s, 1H),7.04 (d, 1H), 6.91 (d, 1H), 5.01 (m, 1H), 4.1 (dd, 2H), 3.52 (dd, 2H),2.79 (m, 2H), 2.67 (m, 2H), 2.46 (s, 3H), 2.43 (s, 3H).

Example 123 Preparation of Compound Nos. 143 and 143a-b

A solution of8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (290 mg,1.31 mmol) and sodium hydride (38 mg, 1.6 mmol) in DMF (6 mL) wasstirred at 120° C. for 1 h. The reaction mixture was cooled to 0° C. and2-(trifluoromethyl)-5-(2-methyloxiran-2-yl)pyridine (400 mg, 1.97 mmol)was added dropwise into the reaction mixture, which was stirred at 120°C. for 2 h. The reaction mixture was cooled to RT and partitionedbetween EtOAc (60 mL) and water (15 mL). The organic layer was separatedand the aqueous layer was extracted with EtOAc (1×20 mL). The combinedorganic layer was washed with water, followed by brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel flash column chromatography to yieldtitle compound. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.79 (s, 1H), 7.21(bs, 1H), 6.97 (s, 1H), 6.79 (d, 1H), 6.42 (bs, 2H), 4.15 (d, 1H), 4.05(d, 1H), 3.2 (m, 3H), 2.99 (s, 1H), 2.74 (d, 1H), 2.56 (t, 1H), 2.45 (s,3H), 1.75 (s, 3H). Separation by chiral HPLC provided enantiomers 143aand 143b.

Example 124 Preparation of Compound Nos. 144 and 144a-b

To a solution of5-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile(1.5 g, 4.3 mmol) in tert-butanol (30 mL) was added crushed KOH (728 mg,13 mmol) and the reaction mixture was stirred at 80° C. for 1 h. Theprogress of reaction was monitored by LCMS. The reaction mixture wasconcentrated. The residue was diluted with water (50 mL) and extractedwith EtOAc (2×100 mL). The combined organic layer was washed with water(2×100 mL), dried over anhydrous sodium sulfate and concentrated. Thecrude material was purified by reverse phase HPLC to yield5-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-pyridine-2-carboxylicacid amide (200 mg). ¹H NMR (CDCl₃, freebase) δ (ppm): 8.45 (d, 1H),8.12 (t, 1H), 7.78 (s, 2H), 7.05 (m, 2H), 6.94 (t, 1H), 5.57 (bs, 1H),5.03 (m, 1H), 4.13 (s, 2H), 3.63 (m, 2H), 2.79 (m, 2H), 2.78 (bs 1H),2.66 (d, 1H), 2.53 (d, 3H), 2.42 (s, 3H). Separation by chiral HPLCprovided enantiomers 144a and 144b.

Example 125 Preparation of Compound Nos. 145 and 145a-b

To an ice-cooled stirred solution of aza dimethyl-carboline (1.8 g, 8.9mmol) in DMF (10 mL) was added sodium hydride (1.0 g, 26.86 mmol, 60%).After stirring at 0° C. for 10 min, 4-(oxiran-2-yl)benzonitrile (2.6 g,17.9 mmol) was added into the reaction mixture, which was stirred at RTfor 16 h. The progress of reaction was monitored by TLC and LCMS. Thereaction mixture was quenched with ice-water and extracted with EtOAc.The organic layer was washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The product wasre-crystallized from EtOH (825 mg). ¹H NMR (CDCl₃, freebase) δ (ppm):8.03 (s, 1H), 7.58 (d, 2H), 7.51 (s, 1H), 7.39 (d, 2H), 7.1 (s 1H), 5.19(m, 1H), 4.4 (dd, 1H), 4.26 (dd, 1H), 3.55 (dd, 2H), 2.75 (m, 1H), 2.64(m 1H), 2.49 (s, 3H), 2.42 (s, 3H), 2.38 (m, 1H). Separation by chiralHPLC provides enantiomers 133a and 133b.

Example 126 Preparation of Compound Nos. 146 and 146a-b

To a solution of1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-yl)propan-2-ol(1.0 g, 2.98 mmol) in DMF (10 mL) was added sodium hydride (60%, 0.36 g,8.95 mmol). After stirring at RT for 10 min, isobutyryl chloride (0.95g, 8.95 mmol) was added dropwise into the reaction mixture, which wasstirred at RT for 15 min. The progress of reaction was monitored by TLC.The reaction mixture was quenched with water (5 mL), basified with sat.aq. sodium bicarbonate and extracted with EtOAc (3×50 mL). The organiclayer was washed with water (3×50 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (0-6% MeOH-DCM) to yieldthe title compound (186.3 mg), which was resolved by chiral preparativeHPLC. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.5 (dd, 1H), 8.42 (s, 1H), 7.24(d, 1H), 7.16 (m, 3H), 6.93 (d 1H), 4.26 (dd, 2H), 3.65 (dd, 2H), 2.7(m, 1H), 2.55 (m, 3H), 2.56 (m, 1H), 2.49 (s 3H), 2.43 (s, 3H), 2.0 (m,1H), 1.98 (s, 3H), 1.1 (m, 6H).

Example 127 Preparation of Compound Nos. 147 and 147a-b

To a solution of isonicotinic acid (200 mg, 1.626 mmol) in DMF (10 mL)was added potassium carbonate (560 mg, 4.065 mmol) and stirred thesolution at 80° C. for 30 min. Methanesulfonic acid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (455 mg, 1.138 mmol) was added portionwise into the reactionmixture, which was stirred at 80° C. 30 min. The progress of reactionwas monitored by LCMS and TLC. The reaction mixture was cooled to RT,diluted with water (30 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layer was washed with water (4×50 mL), dried overanhydrous sodium sulfate and concentrated. The residue was purified byreverse phase HPLC to yield isonicotinic acid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester(30 mg). ¹H NMR (CDCl₃, freebase) δ (ppm): 8.79 (d, 2H), 8.58 (d, 2H),7.77 (d, 2H), 7.23 (d, 1H), 7.18 (s 1H), 7.12 (d, 2H), 7.0 (d, 1H), 6.24(t, 1H), 4.54 (dd, 1H), 4.35 (dd, 1H), 3.68 (s, 2H), 2.76 (t, 2H), 2.61(m, 1H), 2.51 (s, 3H), 2.43 (s, 3H), 2.43 (m, 1H). Separation by chiralHPLC provided enantiomers 147a and 147b.

Example 128 Preparation of Compound Nos. 148 and 148a-d

To a solution of8-aza-10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (500mg, 2.2 mmol) in DMF (5 mL) was added sodium hydride (264 mg, 6.6 mmol).After stirring for 5 min at RT, 2-methyl-5-(2-methyloxiran-2-yl)pyridine(656 mg, 4.4 mmol) was added into the reaction mixture, which wasstirred at RT for 16 h. The progress of reaction was monitored by LCMS.The reaction mixture was quenched with ice-water and extracted withEtOAc. The organic layer was washed with water, dried over anhydroussodium sulfate and concentrated. The residue was purified by reversephase HPLC to yield title compound, which was resolved by chiralpreparative HPLC. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.48 (s, 1H), 8.03(s, 1H), 7.55 (d, 1H), 7.53 (s, 1H), 6.98 (d 1H), 4.41 (d, 1H), 4.23 (d,1H), 3.22 (m, 2H), 3.0 (m, 1H), 2.8 m, 2H), 2.6 (m, 1H), 2.46 (s, 3H),2.41 (s, 3H), 2.34 (m, 2H), 1.88 (m, 2H), 1.63 (s, 3H), 1.58 (m, 1H).

Example 129 Preparation of Compound Nos. 149 and 149a-b

5-(2-Azido-2-(pyridin-3-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Crude) (500 mg, 1.4 mmol) was dissolved in EtOH (4 mL) and water (1mL). Ammonium chloride (243 mg, 4.5 mmol) followed by zinc dust (293 mg,4.5 mmol) were added to the reaction mixture and heated at 80° C. for 1h. The reaction mixture was concentrated to dryness, basified withaqueous ammonia solution and extracted with EtOAc (150 mL). The organiclayer was dried over sodium sulfate, evaporated in vacuo and purified byreverse phase HPLC to afford 2 mg of1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-amine.¹H NMR (CD₃OD, freebase): δ (ppm): 8.39 s (1H), 8.3 d (1H), 7.72 d (1H),7.32 t (1H), 7.11 (1H), 6.91 d (1H), 6.8 d (1H), 4.18 dd (2H), 3.61 dd(2H), 2.7 m (2H), 2.46 s (3H), 2.35 s (3H), 2.26 m (2H). Chiral HPLCprovided enantiomers 149a and 149b.

Example 130 Preparation of Compound Nos. 150 and 150a-b

A solution of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethylmethanesulfonate (250 mg, 0.62 mmol) in dimethyl amine (3 mL, 40% inwater) was stirred at 90° C. for 16 h. The progress of reaction wasmonitored by LCMS. The reaction mixture was lyophilized and crudematerial was purified by reverse phase HPLC. The racemate was furtherseparated into optically active forms by chiral preparative HPLC. ¹H NMR(CDCl₃, freebase) δ (ppm): 8.4 (d, 2H), 7.16 (s, 1H), 7.0 (d, 1H), 6.96(m, 3H), 4.58 (dd, 1H), 4.0 (m, 1H), 3.62 (d, 1H), 3.58 (m, 1H), 3.4(dd, 1H), 2.7 (t, 2H), 2.6 (t, 2H), 2.42 (s, 3H), 2.4 (s, 3H), 2.3 (s,6H).

Example 131 Preparation of Compound Nos. 151 and 151a-b

A solution of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethylmethanesulfonate (250 mg, 0.62 mmol) in methyl amine (3 mL, 40% inwater) was stirred at 90° C. for 12 h. The progress of reaction wasmonitored by LCMS. The reaction mixture was extracted with EtOAc. Theorganic layer was dried and concentrated to get the crude product, whichwas purified by reverse phase HPLC to obtain the2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-N-methyl-1-(pyridin-4-yl)ethanamine.¹H NMR (CDCl₃, freebase): δ (ppm): 8.59 d (2H), 7.3 d (2H), 7.29 d (1H),7.23 s (1H), 7.03 d (1H), 4.19 m (1H), 4.03 m (2H), 3.66 dd (2H), 2.8 m(3H), 2.6 m (1H), 2.55 s (3H), 2.47 s (3H), 2.18 s (3H). Chiral HPLCprovided enantiomers 151a and 151b.

Example 132 Preparation of Compound Nos. 152 and 152a-b

A solution of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethylmethanesulfonate (250 mg, 0.62 mmol) in pyrrolidine (2.5 mL) wasirradiated in microwave at 90° C. for 1 h. The progress of reaction wasmonitored by LCMS. The volatiles were removed under reduced pressure.The residue was diluted with water and extracted with DCM. The organiclayer was dried and concentrated under reduced pressure. The crudematerial was purified by reverse phase HPLC. The racemate was furtherseparated into optically active forms by chiral preparative HPLC. ¹H NMR(CDCl₃, freebase) δ (ppm): 8.39 (d, 2H), 7.16 (s, 1H), 7.0 (d, 1H), 6.97(m, 3H), 4.6 (dd, 1H), 4.0 (m, 1H), 3.79 (d, 1H), 3.6 (d, 1H), 3.57 (dd,1H), 2.7-2.6 (m, 4H), 2.46-2.4 (m, 10H), 1.82 (m, 4H).

Example 133 Preparation of Compound Nos. 153 and 153a-b

To a solution of9-(2-azido-2-(pyridin-4-yl)ethyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(800 mg, 2.3 mmol) in ethanol-water (9 mL: 1 mL) were added zinc dust(600 mg, 9.2 mmol) and ammonium chloride (490 mg, 9.2 mmol) and thereaction mixture stirred at 85° C. for 45 min. The reaction mixture wasfiltered and the filtrate concentrated. The residue was basified withaqueous ammonia and extracted with EtOAc (2×50 mL). The combined organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude material was purified by reverse phase HPLCto yield2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(pyridin-4-yl)ethanamine(25 mg). The racemate can be further separated into the optically activeforms by chiral preparative HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.6(s, 2H), 7.62 (bs, 2H), 7.23 (s, 1H), 7.0 (d, 1H), 6.98 (d, 1H), 4.9 (m,1H), 4.8-4.58 (m, 3H), 4.0 (bs, 1H), 3.8 (bs, 1H), 3.6-3.4 (m, 2H), 3.1(bs, 4H), 2.38 (s, 3H).

Example 134 Preparation of Compound Nos. 154 and 154a-b

To a solution of6-(2-azido-2-(pyridin-4-yl)ethyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(188 mg, 0.522 mmol) in ethanol-water (9 mL: 1 mL), zinc dust (135 mg,2.08 mmol) and ammonium chloride (110 mg, 2.08 mmol) were added and thereaction mixture was stirred at 85° C. for 45 min. The reaction mixturewas filtered and the filtrate concentrated. The residue was basifiedwith aqueous ammonia and extracted with EtOAc (2×50 mL). The combinedorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The crude material was purified by reverse phaseHPLC to yield2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanamine(45 mg). The racemate can be further separated into the optically activeforms by chiral preparative HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.6(d, 2H), 7.6 (d, 2H), 7.22 (s, 1H), 7.0 (s, 1H), 6.9 (s, 1H), 4.9 (m,3H), 4.8 (m, 1H), 4.7 (m, 1H), 3.8-3.6 (m, 2H), 3.2 (m, 2H), 3.18-2.97(m, 4H), 2.8 (bs, 1H), 2.38 (s, 3H).

Example 135 Preparation of Compound Nos. 155 and 155a-d

The azide compound (350 mg, 0.940 mmol) was dissolved in EtOH-water (10mL: 1 mL). Zinc dust (244 mg, 3.763 mmol) and ammonium chloride (199 mg,3.763 mmol) were added and the mixture was heated at 85° C. for 45 min.After consumption of starting material, the reaction mixture wasfiltered through Celite and filtrate was concentrated to obtain theresidue. The residue was basified with aq ammonia and extracted withEtOAc (2×70 mL). The combined organic layer was dried over sodiumsulfate and concentrated to obtain the crude product, which wascrystallized in diethyl ether to obtain 150 mg of desired product. ¹HNMR (CDCl₃, freebase): δ (ppm): 8.55 d (2H), 7.29 d (2H), 7.25 d (1H),7.2 s (1H), 7.02 d (1H), 4.77 m (2H), 4.49 t (1H), 4.1 m (1H), 4.08 m(2H), 3.51 m (1H), 2.7 dd (1H), 2.46 s (3H), 2.25 s (3H), 2.2 m (1H),1.86 t (1H), 1.44 t (1H). Chiral HPLC provided enantiomers 155a and155b.

Example 136 Preparation of Compound Nos. 156 and 156a-b

To a solution of5-(2-azido-2-(pyridin-4-yl)ethyl)-2,8-dimethyl-6-aza-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(160 mg, 0.461 mmol) in EtOH:water (4:0.4 mL) were added zinc dust(119.8 mg, 1.84 mmol) and ammonium chloride (99.59 mg, 1.84 mmol) andthe reaction mixture was stirred at 80° C. for 1 h. The progress ofreaction was monitored by NMR. The mixture was filtered and the filtrateconcentrated under reduced pressure. The residue was basified withaqueous ammonia and extracted with EtOAc. The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by reverse phase HPLC to yield the titlecompound. The racemate can be further separated into the opticallyactive forms by chiral preparative HPLC. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 8.8 (m, 2H), 8.19 (s, 1H), 7.9 (m, 2H), 7.7 (s, 1H), 5.3 (m, 1H),4.8 (m, 2H), 4.63 (d, 1H), 4.25 (d, 1H), 3.85 (m, 1H), 3.5 (m, 1H), 3.2(m, 2H), 3.17 (s, 3H), 2.4 (s, 3H).

Example 137 Preparation of Compound Nos. 157 and 157a-b

To a solution of5-[1-amino-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-pyridine-2-carbonitrile(400 mg, 1.15 mmol) in tert-butanol (20 mL) was added crushed KOH (194mg, 3.47 mmol) and the reaction mixture was stirred at 80° C. for 1 h.The progress of reaction was monitored by LCMS. The reaction mixture wasconcentrated to dryness. The residue was diluted with water (50 mL) andextracted with EtOAc (2×100 mL). The combined organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by reverse phase HPLC to yield5-[1-amino-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-pyridine-2-carboxylicacid amide (70 mg). The racemate can be further separated into theoptically active forms by chiral preparative HPLC. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.5 (s, 1H), 8.2 (d, 1H), 7.9 (d, 1H), 7.2 (m, 2H), 7.0(d, 1H), 5.6 (bs, 1H), 4.6 (t, 1H), 4.1 (d, 2H), 3.7 (q, 2H), 2.9 (t,2H), 2.8 (m, 1H), 2.6 (m, 1H), 2.58 (s, 3H), 2.42 (s, 3H).

Example 138 Preparation of Compound Nos. 158 and 158a-b

To a solution of5-(2-azido-2-(pyridin-4-yl)ethyl)-8-methyl-6-aza-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(730 mg, 2.19 mmol) in EtOH:H2O (15:1.5 mL) were added zinc dust (570mg, 8.76 mmol) and ammonium chloride (473.5 mg, 8.76 mmol) and thereaction mixture was stirred at 80° C. for 1 h. The progress of reactionwas monitored by NMR. The mixture was filtered and the filtrateconcentrated under reduced pressure. The residue was basified withaqueous ammonia and extracted with EtOAc. The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by reverse phase HPLC to yield the titlecompound. The racemate can be further separated into the opticallyactive forms by chiral preparative HPLC. ¹H NMR (CDCl₃, free base) δ(ppm): 8.5 (d, 2H), 8.08 (s, 1H), 7.5 (s, 1H), 7.21 (d, 2H), 4.6 (t,1H), 4.3 (dd, 1H), 4.2 (dd, 1H), 4.0 (s, 2H), 3.1 (m, 2H), 2.6 (d, 1H),2.4 (s, 3H), 2.3 (d, 1H).

Example 139 Preparation of Compound Nos. 159 and 159a-b

To a degassed solution of4-(1-azido-2-(6-aza-2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethyl)benzonitrile(240 mg) in EtOAc:EtOH (7:7 mL) was added 10% Pd—C (100 mg), andhydrogen gas was bubbled into the reaction mixture with stirring at RTfor 5 h. The progress of reaction was monitored by LCMS. The reactionmass was filtered through Celite and the filtrate concentrated underreduced pressure. The residue was purified through reverse phase HPLC toyield the racemate (200 mg), which was separated by chiral preparativeHPLC. ¹H NMR (CDCl₃, free base) δ (ppm): 8.05 (s, 1H), 7.6 (d, 2H), 7.43(m, 3H), 4.6 (t, 1H), 4.23 (dd, 2H), 3.7 (dd, 2H), 2.9 (m, 1H), 2.8 (m,2H), 2.6 (s, 3H), 2.5 (m, 1H), 2.4 (s, 3H).

Example 140 Preparation of Compound Nos. 160 and 160a-b

To a degassed solution of4-(1-azido-2-(6-aza-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethyl)benzonitrile(219 mg) in EtOAc:EtOH (7:7 mL) was added 10% Pd—C (100 mg), andhydrogen gas was bubbled into the reaction mixture with stirring at RTfor 5 h. The progress of reaction was monitored by LCMS. The reactionmass was filtered through Celite and the filtrate concentrated underreduced pressure. The residue was purified through reverse phase HPLC toyield the racemate, which was separated by chiral preparative HPLC. ¹HNMR (CDCl₃, free base) δ (ppm): 8.1 (s, 1H), 7.6 (d, 2H), 7.47 (m, 3H),4.6 (t, 1H), 4.2 (m, 2H), 4.18 (s, 2H), 3.21 (bm, 1H), 2.8 (bm, 1H),2.7-2.6 (m, 2H), 2.6 (s, 3H).

Example 141

Compound Nos. 161, 161a-d, 162, 162a-d, 163, 163a-d, 164, 164a-d, 165,165a-b, 166, 166a-b, 167, 167a-b, 171 and 171a-b can be prepared inanalogous fashion to Compound Nos. 3 and 3a-b, using appropriatelyfunctionalized aromatic-tethered oxiranes as reagents. Compound Nos.173, 174, 175 and 176 were prepared in analogous fashion to CompoundNos. 3 and 3a-b, using appropriately functionalized aromatic-tetheredoxiranes as reagents. Chiral HPLC provided, respectively, Compound Nos.173a-b, 174a-b, 175a-b and 176a-d.

Example 142 Preparation of Compound Nos. 168 and 168a-d

To a solution of4-[1-hydroxy-2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-ethyl]-pyridine-2-carbonitrile(68 mg, 0.18 mmol) in 1 mL THF was added NaOH (21 mg, 0.52 mmol) i.e.0.5 mL 1M NaOH solution and was heated at 80° C. for overnight. Thereaction was monitored with LCMS. The solvent was removed under reducedpressure to obtain the crude product that was purified by reverse phaseHPLC to obtain pure product as the TFA salt (8 mg). ¹H NMR (CD₃OD, TFAsalt): δ (ppm): 8.55 t (1H), 7.95 d (1H), 7.61 d (1H), 7.25 s (1H), 7.2dd (1H), 7.01 dd (1H), 5.16 m (1H), 5.03 m (1H), 4.36 m (2H), 3.61 m(3H), 3.3 m (1H), 2.7 m (2H), 2.4 d (3H), 2.2 m (3H). Chiral HPLCprovides diastereomers 168a-d.

Example 143 Preparation of Compound Nos. 169 and 169a-b

A solution of5-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridine-2-carbonitrile(1.6 g) in ethanol (4 mL) and 10 N NaOH (15 mL) was stirred at 100° C.for 45 min. The progress of reaction was monitored by TLC and LCMS. Thereaction mixture was lyophilized and purified with reverse phase HPLC toobtain the5-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridine-2-carboxylicacid. ¹H NMR (CD₃OD, TFA salt): δ (ppm): 8.6 d (1H), 8.1 s (1H), 8.0 d(1H), 7.19 d (1H), 6.9 d (1H), 6.8 d (1H), 4.7 dd (1H), 4.37 m (2H), 4.3m (1H), 3.8 m (1H), 3.52 m (2H), 3.15 m (1H), 3.1 s (3H), 2.38 s (3H),1.7 d (3H). Chiral HPLC provides enantiomers 169a and 169b.

Example 144 Preparation of Compound Nos. 170 and 170a-b

These compounds can be prepared in analogous fashion to Compound Nos. 67and 67a-b, using ethyl5-(1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxypropan-2-yl)nicotinateas starting material. Separation by chiral HPLC provides enantiomers170a-b.

Example 145 Preparation of Compound Nos. 177 and 177a-d

These compounds can be prepared in analogous fashion to Compound Nos. 67and 67a-b, using ethyl4-(1-hydroxy-2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)ethyl)nicotinateas starting material. Separation by chiral HPLC provides diastereomers177a-d.

Example 146 Preparation of Compound Nos. 178 and 178a-b

These compounds can be prepared in analogous fashion to Compound Nos. 67and 67a-b, using ethyl3-(1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxypropan-2-yl)picolinateas starting material. Separation by chiral HPLC provides enantiomers178a-b.

Example 147 Preparation of Compound Nos. 179 and 179a-b

3-(1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxypropan-2-yl)isonicotinonitrile(200 mg, 0.554 mmol) was dissolved in ethanol and an aqueous solution ofsodium hydroxide was added and heated at 100° C. for 1 h. The reactionwas monitored by LCMS. After completion of reaction, solvent was removedunder reduced pressure and the crude product was purified by reversephase HPLC (8 mg). ¹H NMR (CD₃OD, freebase): 9.3 s (1H), 8.42 s (1H),8.3 s (1H), 7.4 d (1H), 7.1 s (1H), 6.8 d (1H), 4.4 s (2H), 4.2 m (2H),3.58 m (2H), 3.55 m (1H), 3.3 m (1H), 3.1 s (3H), 2.4 s (3H), 1.54 s(3H). Chiral separation provides enantiomers 179a and 179b.

Example 148 Preparation of Compound Nos. 46 and 46a-b

These compounds can be prepared in analogous fashion to Compound Nos. 67and 67a-b, using ethyl3-(1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxypropan-2-yl)picolinateas starting material. Separation by chiral HPLC provides enantiomers46a-b.

Example 149 Preparation of Compound Nos. 50 and 50a-d

These compounds can be prepared in analogous fashion to Compound Nos. 67and 67a-b, using ethyl4-(1-ethoxy-2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)ethyl)nicotinateas starting material. Separation by chiral HPLC provides diastereomers50a-d.

Example 150 Preparation of Compound Nos. 104 and 104a-b

These compounds can be prepared in analogous fashion to Compound Nos. 67and 67a-b, using ethyl4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-hydroxy-3-(pyridin-3-yl)butanoateas starting material. Separation by chiral HPLC provides enantiomers104a-b.

Example 151 Preparation of Compound Nos. 123 and 123a-b

These compounds can be prepared in analogous fashion to Compound Nos. 67and 67a-b, using ethyl5-(1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxypropan-2-yl)nicotinateas starting material. Separation by chiral HPLC provides enantiomers123a-b.

Example 152 Preparation of Compound No. 180

2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol),4-methylstyrene (239 mg, 2.3 mmol) and NaH (120 mg, 60% dispersion inoil, 3 mmol) were heated in DMSO (4 mL) at 120° C. overnight (16 h)after which methanol was added and the contents were concentrated todryness. The resulting crude product was purified by reverse-phasechromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water,B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min,injection vol: 5 mL) and/or silica gel (230-400 mesh) chromatographyeluting with methanol-dichloromethane gradient to obtain 20 mg (6.2%yield) of2,3,4,5-tetrahydro-2,8-dimethyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indoleas a trifluoroacetate salt. ¹H NMR (CDCl₃, TFA salt) δ (ppm): 13.3 (bs,1H), 7.4-7.0 (m, 5H), 6.80-6.70 (d, 2H), 4.7-4.6 (d, 1H), 4.40-4.22 (m,1H), 4.20-4.10 (m, 1H), 4.10-4.0 (d, 1H), 3.5-3.4 (t, 1H), 3.20-3.17 (t,1H), 3.0 (t, 2H), 2.80 (s, 3H), 2.7-2.61 (m, 1H), 2.40 (s, 3H), 2.23 (s,3H), 2.2-2.1 (m, 1H).

Example 153 Preparation of Compound No. 181

2,3,4,5-Tetrahydro-2-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indolewas prepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(200 mg, 1.07 mmol), 4-methylstyrene (1.41 mL, 10.7 mmol) and NaH (250mg, 60% dispersion in oil, 6.25 mmol) in DMF (6 mL) at 200° C. for 16 hto obtain 7 mg of2,3,4,5-tetrahydro-2-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indoleafter purification. ¹H NMR (CDCl₃, TFA salt) δ (ppm): 7.45-7.40 (d, 2H),7.25-7.16 (m, 2H), 7.1-6.9 (d, 2H), 6.8-6.7 (d, 2H), 4.7 (d, 1H),4.4-4.3 (m, 1H), 4.20-4.03 (m, 2H), 3.55-3.40 (m, 1H), 3.22-3.10 (m,1H), 3.09-2.90 (m, 2H), 2.83 (s, 3H), 2.65 (m, 1H), 2.35 (s, 3H), 2.2(m, 1H).

Example 154 Preparation of Compound No. 182

2,3,4,5-Tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indole wasprepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200mg, 1.07), styrene (1.23 mL mmol, 10.65) and NaH (250 mg, 6.25 mmol) inDMF (6 mL) at 200° C. for 16 h to obtain 15 mg of2,3,4,5-tetrahydro-2-methyl-5-phenethyl-1H-pyrido[4,3-b]indole afterpurification. ¹H NMR (CDCl₃, TFA salt) δ (ppm): 7.5-7.10 (m, 7H),6.9-6.8 (m, 2H), 4.6 (d, 1H), 4.30-4.19 (m, 2H), 4.05 (d, 1H), 3.62-3.40(m, 1H), 3.20-3.0 (m, 3H), 2.9 (s, 3H), 2.7-2.6 (t, 1H), 2.2-2.1 (t,1H).

Example 155 Preparation of Compound Nos. 183 and 183a-b

3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (2.2 g, 11 mmol, 1equiv.), 4-methylstyrene oxide (5.8 g, 44 mmol, 4 equiv.) and NaH (1.3g, 32.5 mmol, 2.95 eq) were heated in DMF (70 mL) at 120° C. for 16 h(overnight). The contents were quenched by MeOH and evaporated todryness. The resulting crude product was purified by silica gelchromatography (230-400 mesh) using EtOAc-hexane gradient to obtain 1.3g ofracemic-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol.The free base was converted into its hydrochloride salt by treatment ofethanolic HCl. ¹H NMR (DMSO-d6, HCl salt) δ (ppm): 10.30 (s, 1H),7.42-7.0 (m, 7H), 5.6 (m, 1H), 4.90-4.80 (m, 1H), 4.60-4.55 (d, 1H),4.30-4.00 (m, 3H), 3.70 (s, 1H), 3.4 (m, 1H), 3.22-3.10 (d, 1H),3.00-2.90 (m, 3H), 2.80-2.60 (d, 1H), 2.40 (s, 3H), 2.30 (s, 3H).Separation by chiral HPLC provided enantiomers 183a and 183b.

Example 156 Preparation of Compound No. 184

5-(4-Chlorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indolewas prepared from 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(500 mg, 2.5 mmol), 4-chlorostyrene (3.18 mL, 25 mmol) and NaH (300 mg,7.5 mmol) in DMF (10 mL) at 180° C. overnight (16 h) to obtain 15 mg of5-(4-chlorophenethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indoleafter purification. ¹H NMR (CDCl₃, TFA salt) δ (ppm): 7.30-7.08 (m, 5H),6.85-6.78 (d, 2H), 4.70-4.60 (d, 1H), 4.40-4.20 (m, 1H), 4.20-4.0 (m,2H), 3.65-3.50 (m, 1H), 3.10-3.00 (m, 3H), 2.85 (s, 3H), 2.80 (m, 1H),2.45 (s, 3H), 2.2 (m, 1H).

Example 157 Preparation of Compound No. 185

1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol(1 equiv.) was refluxed with 25% sulfuric acid for 2 h. The reactionmixture was cooled to 5° C. with an ice-water bath. KOH (15% aq.solution) was added dropwise to the reaction mixture until pH 9-10 wasachieved. The reaction mixture was extracted with EtOAc. The combinedorganic layers were washed with water followed by brine, dried overanhydrous sodium sulfate and evaporated under vacuum. The crude productwas purified by column chromatography over silica gel (100-200 mesh)using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of8-chloro-2,3,4,5-tetrahydro-2-methyl-5-((E)-2-(pyridin-4-yl)prop-1-enyl)-1H-pyrido[4,3-b]indoleand8-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-4-yl)allyl)-1H-pyrido[4,3-b]indole,which were separated by HPLC. ¹HNMR (DMSO, Oxalate Salt) δ (ppm): 8.60(d, 2H), 7.62 (m, 3H), 7.40 (s, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 4.40(m, 2H), 3.10 (m, 4H), 2.99 (s, 3H), 1.90 (s, 3H).

Example 158 Preparation of Compound No. 186

1-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(6-methylpyridin-3-yl)propan-2-ol(1 equiv.) was refluxed with 25% sulfuric acid for 2 h. The reactionmixture was cooled to 5° C. with an ice-water bath. KOH (15% aq.solution) was added dropwise to the reaction mixture until pH 9-10 wasachieved. The reaction mixture was extracted with EtOAc. The combinedorganic layers were washed with water followed by brine, dried overanhydrous sodium sulfate and evaporated under vacuum. The crude productwas purified by column chromatography over silica gel (100-200 mesh)using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of2,3,4,5-tetrahydro-2,8-dimethyl-5-((E)-2-(6-methylpyridin-3-yl)prop-1-enyl)-1H-pyrido[4,3-b]indoleand2,3,4,5-tetrahydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)allyl)-1H-pyrido[4,3-b]indole,which were separated by HPLC. ¹HNMR (CD₃OD, TFA salt) δ (ppm) 8.90 (s,1H), 8.60 (d, 1H), 7.80 (d, 1H), 7.30 (d, 2H), 7.16 (d, 1H), 7.10 (d,1H), 4.78 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.20 (m,2H), 3.16 (s, 3H), 3.80 (s, 3H), 2.42 (s, 3H), 2.05 (s, 3H).

Example 159 Preparation of Compound No. 187

To a solution of1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg, 0.257 mmol) in DME (4 mL) was addedPd(PPh₃)₄ (15 mg, 0.0128 mmol) and the solution was purged with nitrogenfor 5 min. Potassium carbonate (36 mg, 0.257 mmol), water (2 mL) and2-(dimethylamino)-pyrimidine-5-boronic acid pinacol ester (128 mg, 0.515mmol) were added, the reaction mixture was purged with nitrogen andrefluxed for 45 min. The reaction mixture was cooled to RT and thesolvent evaporated under reduced pressure. The residue was dissolved inEtOAc and filtered. The filtrate was concentrated under reduced pressureand purified by reverse phase HPLC to obtain the desired product as itsTFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.78 (s, 2H), 7.31 (s, 1H),7.10 (m, 3H), 4.78 (d, 1H), 4.38 (d, 1H), 3.82 (m, 1H), 3.59 (m, 1H),3.38 (s, 6H), 3.10 (m, 5H), 2.41 (s, 3H), 1.97 (s, 3H).

Example 160 Preparation of Compound No. 188

5-(1-Bromoprop-1-en-2-yl)-2-methylpyridine (254 mg, 1.2 mmol) wasdissolved in DMF (2 mL) and potassium phosphate (424 mg, 2 mmol), copper(I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol) were added,followed by 2,3,4,5-tetrahydro-2,6,8-trimethyl-1H-pyrido[4,3-b]indole(214 mg, 1 mmol). The reaction mixture was purged with nitrogen andheated at 140° C. overnight. The reaction mixture was cooled to RT,diluted with ice water and extracted with EtOAc (3×15 mL). The combinedorganic layer was washed with water (2×10 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (100-200 mesh) eluting with 0-6%MeOH:DCM. The compound was further purified by reverse phase HPLC toobtain 37 mg of product as a freebase. The free base was converted intoHCl salt by treatment with ethanolic HCl. ¹H NMR (CD₃OD, HCl salt) δ(ppm): 8.98 (s, 1H), 8.78 (d, 1H), 8.0 (d, 1H), 7.6 (s, 1H), 7.17 (s,1H), 6.82 (s, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.82 (m, 1H), 3.61 (m, 1H),3.18 (m, 5H), 2.90 (s, 3H), 2.51 (s, 3H), 2.38 (s, 3H), 2.01 (s, 3H).

Example 161 Preparation of Compound No. 189

To a degassed solution of[(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate] (100 mg, 0.257 mmol) in DME (4 mL) were addedPd(PPh₃)₄ (15 mg, 0.0128 mmol), potassium carbonate (36 mg, 0.257 mmol),water (2 mL) and 3-methylthiophene-2-boronic acid pinacol ester (115 mg,0.515 mmol) followed by nitrogen purging. The reaction mixture wasrefluxed for 45 min. At that point, TLC showed no starting materialremaining. The reaction mixture was cooled to RT and the solventevaporated under reduced pressure. The residue was dissolved in EtOAcand filtered through a sintered crucible. The filtrate was concentratedunder vacuum and the product isolated by reverse phase HPLC. ¹H NMR,(CD₃OD, TFA salt) δ (ppm): 7.32 (m, 2H), 7.13 (m, 2H), 6.97 (d, 1H),6.79 (s, 1H), 4.67 (d, 1H), 4.40 (d, 1H), 3.83 (m, 1H), 3.58 (m, 1H),3.14 (m, 5H), 2.40 (s, 6H), 1.87 (s, 3H).

Example 162 Preparation of Compound No. 190

To a degassed solution of5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.29 mmol), 5-methylthiophene-2-boronic acid pinacol ester (100mg, 0.575 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-DME(4 mL) and water (2 mL) was added Pd(PPh₃)₄ (17 mg, 0.0147 mmol). Thereaction mixture was heated at 90° C. for 45 min. The reaction mixturewas concentrated under reduced pressure and the residue diluted withwater (20 mL) and extracted with EtOAc (50 mL). The organic layer wasdried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was purified by reverse phase HPLC to yield2,8-dimethyl-5-(2-(5-methylthiophen-2-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR, (CD₃OD, TFA salt) δ (ppm): 7.3 (s, 1H), 7.0 (m, 2H), 6.71 (d,1H), 6.58 (d, 1H), 4.72 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.51 (m, 1H),3.12 (s, 3H), 3.03 (m, 4H), 2.8 (m, 2H), 2.4 (s, 3H), 2.2-2.3 (m, 5H).

Example 163 Preparation of Compound No. 191

To a degassed solution of5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.29 mmol), 1-methylindole-5-boronic acid pinacol ester (149mg, 0.579 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-DME(4 mL) and water (2 mL) was added Pd(PPh₃)₄ (17 mg, 0.0147 mmol). Thereaction mixture was heated at 90° C. for 45 min. The reaction mixturewas concentrated under reduced pressure. The residue was diluted withwater (20 mL) and extracted with EtOAc (50 mL). The organic layer wasdried over anhydrous sodium sulfate and evaporated. The residue waspurified by reverse phase HPLC to yield2,8-dimethyl-5-(2-(1-methyl-1H-indol-5-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR, (CD₃OD, TFA salt) δ (ppm): 7.21-7.38 (m, 2H), 7.2 (s, 1H), 7.04(m, 2H), 6.9 (d, 1H), 6.8 (d, 1H), 6.21 (s, 1H), 4.62 (m, 1H), 4.35 (m,1H), 3.65 (s, 3H), 3.58 (m, 2H), 3.01 (s, 3H), 2.81 (m, 2H), 2.6 (m,4H), 2.41 (s, 3H), 2.21 (m, 2H).

Example 164 Preparation of Compound Nos. 192 and 192a-d

To a solution of ethyl4-(1-hydroxy-2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)ethyl)picolinate(1 eq) in EtOH is added sodium hydroxide (4 eq, in water) and heated to65° C. After conversion of starting material (TLC and LCMS), the EtOHand water are removed under reduced pressure. The crude product ispassed through HPLC to yield the title racemic compound. Separation bychiral HPLC provides enantiomers 192a-d.

Example 165 Preparation of Compound Nos. 193 and 193a-b

To a degassed solution of10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (50 mg,0.22 mmol), potassium phosphate (93 mg, 0.44 mmol), L-proline (2 mg,0.01 mmol) and Cu(I)iodide (8 mg, 0.04 mmol) in DMF (1 mL) was added5-(1-bromoprop-1-en-2-yl)-2-methylpyridine (93 mg, 0.44 mmol). Thereaction mixture was stirred at 120° C. for 18 h. The progress ofreaction was monitored by TLC and LCMS. The reaction mixture wasfiltered through Celite and the filtrate was diluted with water (50 mL),extracted with EtOAc (2×50 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by reverse phase HPLC to yield10-methyl-7-(2-(6-methylpyridin-3-yl)prop-1-enyl)-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole.¹H NMR, (CD₃OD, formate salt) δ (ppm): 8.65 (s, 1H), 8.0 (d, 1H), 7.4(d, 1H), 7.35 (s, 1H), 7.15 (d, 1H), 7.08 (d, 2H), 5.0 (t, 1H), 3.6 (m,3H), 3.4 (m, 1H), 3.09 (q, 2H), 2.85 (m, 1H), 2.6 (s, 3H), 2.42 (s, 3H),2.2 (m, 3H), 2.0 (s, 3H). Chiral HPLC provided the enantiomers 193a and193b.

Example 166 Preparation of Compound Nos. 194 and 194a-b

To a degassed solution of10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (50 mg,0.22 mmol), potassium phosphate (93 mg, 0.44 mmol), L-proline (2 mg,0.01 mmol) and Cu(I)iodide (8 mg, 0.04 mmol) in DMF (1 mL) was added1-(1-bromoprop-1-en-2-yl)-4-fluorobenzene (95 mg, 0.44 mmol). Thereaction mixture was stirred at 120° C. for 18 h. The progress ofreaction was monitored by TLC and LCMS. The reaction mixture wasfiltered through Celite. The filtrate was diluted with water (50 mL),extracted with EtOAc (2×50 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by reverse phase HPLC to yield7-(2-(4-fluorophenyl)prop-1-enyl)-10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole.¹H NMR, (CD₃OD, TFA salt) δ (ppm): 7.65 (t, 2H), 7.35 (s, 1H), 7.19 (t,2H), 7.1 (m, 2H), 6.95 (s, 1H), 5.1 (t, 1H), 3.79 (m, 1H), 3.62 (m, 2H),3.41 (m, 1H), 3.1 (m, 2H), 2.75 (m, 1H), 2.41 (s, 3H), 2.28 (m, 3H),1.95 (s, 3H). Chiral HPLC provided the enantiomers 194a and 194b.

Example 167 Preparation of Compound Nos. 195 and 195a-b

This compound is prepared in analogous fashion to Compound Nos. 30 and30a-b, using 5-(2-methyloxiran-2-yl)oxazole as the oxirane reagent.Separation by chiral HPLC provides enantiomers 195a-b.

Example 168 Preparation of Compound Nos. 196 and 196a-b

To a stirred solution of2,3,4,9-tetrahydro-2,6-dimethyl-1H-pyrido[3,4-b]indole (500 mg, 2.5mmol) in DMF (2 mL) was added NaH (300 mg, 7.5 mmol). After stirring for5 min, a solution of 2-methyl-5-(2-methyloxiran-2-yl)pyridine (558 mg,3.7 mmol) in DMF (1 mL) was added and the reaction mixture stirred at RTfor 16 h. The progress of reaction was monitored by TLC and LCMS. Thereaction mixture was quenched with ice-water and extracted with EtOAc.The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by reversephase HPLC to yield the title compound. The product was further purifiedby chiral HPLC separation to give enantiomers 196a and 196b. ¹H NMR,(CDCl₃, freebase) δ (ppm): 8.6 (s, 1H), 7.6 (d, 1H), 7.27 (s, 1H), 7.1(d, 1H), 7.05 (d, 1H), 6.9 (d, 1H), 4.1 (d, 1H), 4.0 (d, 1H), 3.62 (d,1H), 3.43 (d, 1H), 2.8 (m, 4H), 2.59 (s, 3H), 2.5 (s, 3H), 2.4 (s, 3H),1.6 (s, 3H).

Example 169 Preparation of Compound Nos. 197 and 197a-b

To a solution of9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene(100 mg, 0.422 mmol) in DMF (1 mL) was added sodium hydride (53 mg,1.326 mmol). After stirring for 5 min, a solution of toluene-4-sulfonicacid 2-(6-methyl-pyridin-3-yl)-ethyl ester (386 mg, 1.326 mmol) in DMF(1 mL) was added dropwise at 0° C. and the reaction mixture stirred atRT for 6 h. The progress of reaction was monitored by TLC and LCMS. Thereaction mixture was poured into ice-cold water and extracted with EtOAc(3×25 mL). The combined organic layer was washed with water (5×20 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by reverse phase HPLC to yield9-methyl-6-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene.¹H NMR, (CDCl₃, freebase) δ (ppm): 8.07 (s, 1H), 7.28 (m, 2H), 7.07 (d,1H), 7.0 (s, 2H), 4.72 (m, 1H), 4.3 (m, 1H), 4.18 (m, 1H), 3.31 (m, 1H),3.2 (m, 1H), 3.12 (m, 1H), 3.0 (m, 2H), 2.7 (m, 1H), 2.51 (m, 1H), 2.5(s, 3H), 2.48 (s, 3H), 2.4 (d, 1H), 2.28 (m, 1H), 2.2 (m, 1H), 2.0 (m,1H), 1.8 (m, 1H). Chiral HPLC provided enantiomers 197a and 197b.

Example 170 Preparation of Compound Nos. 198 and 198a-d

To a solution of9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene(200 mg, 0.88 mmol) in DMF (10 mL) was added sodium hydride (96 mg, 2.6mmol). After stirring for 5 min, a solution of2-methyl-5-oxiranyl-pyridine (175 mg, 1.3 mmol) in DMF (1 mL) was addeddropwise into the reaction mixture, which was stirred at RT for 5 h. Theprogress of reaction was monitored by TLC and LCMS. The reaction mixturewas poured into ice-cold water and extracted with EtOAc (3×25 mL). Thecombined organic layer was washed with water (5×25 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by reverse phase HPLC to yield2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-(6-methyl-pyridin-3-yl)-ethanol.The product was further purified by chiral HPLC separation to giveenantiomers 198a and 198b. Enantiomers 198c and 198d are also obtainedby this method. ¹H NMR, (CDCl₃, freebase) δ (ppm): 8.45 (s, 1H), 7.6(dd, 1H), 7.22 (m, 2H), 7.1 (t, 1H), 7.05 (t, 1H), 5.08 (q, 1H), 4.8(dt, 1H), 3.5 (m, 2H), 3.4 (m, 2H), 3.1 (d, 1H), 3.0 (m, 1H), 2.8 (m,1H), 2.6 (m, 2H), 2.5 (s, 3H), 2.41 (s, 3H), 2.1 (m, 3H).

Example 171 Preparation of Compound Nos. 199 and 199a-b

To a degassed solution of11-methyl-1,2,3,4,6,7,8,12c-octahydroindolo[3,2-a]quinolizine (100 mg,0.41 mmol), copper(I)iodide, L-proline (9.6 mg, 0.08 mmol) and potassiumphosphate (176 mg, 0.83 mmol) in DMF was added dropwise1-(1-bromoprop-1-en-2-yl)-4-fluorobenzene (107 mg, 53 mmol) and thereaction mixture was stirred at 85° C. overnight. The DMF was evaporatedunder reduced pressure, and the residue was diluted with water and thesolid filtered. The solid material was purified by silica gelchromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The productwas further purified by reverse phase HPLC followed by chiral HPLCseparation to give enantiomers 199a and 199b. ¹H NMR, (CDCl₃, freebase)δ (ppm): 7.5 (t, 2H), 7.4 (s, 1H), 7.1 (t, 2H), 7.08 (d, 1H), 7.0 (d,1H), 6.8 (s, 1H), 3.5 (m, 1H), 3.4 (m, 1H), 3.0 (m, 2H), 2.6 (m, 3H),2.4 (s, 3H), 2.05 (m, 1H), 2.0 (s, 3H), 1.8 (m, 2H), 1.5 (m, 3H).

Example 172

Compound Nos. 200-210, 212-219 and 223 were prepared as described in PCTpublication WO2009-055828.

Example 173

Compound Nos. 211, 225 and 231 were prepared as described in PCTpublication WO2009-120720.

Example 174

Compound Nos. 224 and 239 were prepared as described in PCT publicationWO2009-120717.

Example 175

Compound Nos. 236-237, 243, 250, 252-254, 256-259 and 261-268 wereprepared as described in PCT publication WO2010-051501.

Example 176

Compound Nos. 172, 221-222, 226-230, 232-235, 238, 240-242, 244-249 and251 were prepared as described in PCT publication WO2010-051503.

Example 177

Compound Nos. 255 and 260 were prepared as described in PCT publicationWO2010-127177.

Example 178 Preparation of Compound Nos. 220 and 220a-b

This compound is prepared in analogous fashion to Compound Nos. 30 and30a-b, using 4-(2-methyloxiran-2-yl)oxazole as the oxirane reagent.Separation by chiral HPLC provides enantiomers 220a-b.

Example 179 Preparation of Compound No. 269

To a degassed solution of2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.08 g, 0.0004mol), potassium tert-butoxide (0.112 g, 0.001 mol),(E/Z)-4-(1-bromoprop-1-en-2-yl)-2-methoxypyridine (0.091 g, 0.0004 mol)and 9,9-dimethyl-4,5-bis(diphenylphosphine) xanthene (0.023 g, 0.00004mol) in toluene (3 mL) was added Pd₂(dba)₃ (0.0219 g, 0.000064 mol) andirradiated the reaction mixture at 80° C. for 30 min. The reactionmixture was diluted with water (30 mL) and extracted with EtOAc (3×20mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (2% MeOH-DCM) followed by preparative TLC toyield the title compound. ¹H NMR (CD₃OD, Oxalate salt) δ (ppm): 8.19 (d,1H), 7.27 (s, 1H), 7.24 (m, 2H), 7.05 (m, 2H), 7.0 (s, 1H), 4.58 (s,3H), 3.93 (s, 3H), 3.65 (m, 2H), 3.17 (m, 4H), 2.41 (s, 3H), 2.01 (s,3H).

Example 180 Preparation of Compound No. 270

To a degassed solution of1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)prop-1-en-2-yltrifluoromethanesulfonate (50 mg, 0.129 mmol), Pd(PPh₃)₄ (7.4 mg,0.0064) in DME (2 mL) were added potassium carbonate (17.8 mg, 0.1287mmol), water (1 mL) and naphthalene-2-boronic acid (44 mg, 0.258 mmol)and the reaction mixture refluxed for 45 min. The reaction mixture wascooled to RT, and the solvent was removed under reduced pressure. Theresidue was dissolved in water (10 mL), extracted into EtOAc (3×25 mL)and washed with brine. The organic layer was dried over anhydrous sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (2.5% MeOH-DCM) to yield the title compound. ¹H NMR(CD₃OD, freebase) δ (ppm): 8.02 (s, 1H), 7.82 (m, 3H), 7.79 (d, 1H),7.42 (m, 2H), 7.21 (s, 1H), 7.11 (m, 2H), 6.95 (m, 1H), 3.78 (s, 2H),2.84 (m, 4H), 2.60 (s, 3H), 2.40 (s, 3H), 2.12 (s, 3H).

Example 181 Preparation of Compound No. 271

To a degassed solution of1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)prop-1-en-2-yltrifluoromethanesulfonate (50 mg, 0.129 mmol) and Pd(PPh₃)₄ (7.4 mg,0.0064) in DME (2 mL) were added potassium carbonate (17.8 mg, 0.1287mmol), water (1 mL) and naphthalene-2-boronic acid (44 mg, 0.258 mmol),and the reaction mixture refluxed for 45 min. The reaction mixture wascooled to RT, and the solvent was removed under reduced pressure. Theresidue was dissolved in water (10 mL), extracted into EtOAc (3×25 mL),washed with brine, and concentrated to afford crude material, which waspurified by silica gel column chromatography (2.5% MeOH-DCM) to yieldthe desired compound. ¹H NMR (CD₃OD, freebase) δ (ppm): 7.64 (m, 3H),7.34 (m, 1H), 7.29 (m, 2H), 7.18 (m, 2H), 6.97 (m, 1H), 6.82 (m, 2H),3.67 (s, 2H), 2.63 (d, 2H), 2.38-2.47 (m, 8H), 1.84 (s, 3H).

Example 182 Preparation of Compound Nos. 272 and 272a-b

A solution of8-chloro-5-(2-(4-fluorophenyl)allyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(150 mg, 0.423 mmol) and 10% Pd/C (10 mg) in MeOH:acetic acid (9 mL,10:1) was hydrogenated in a Parr shaker at RT and 50 psi for 18 h. Thereaction mixture was filtered through a Celite bed and the filtrateconcentrated under reduced pressure. The residue was purified by reversephase HPLC to yield the title compound. The product was further purifiedby reverse phase HPLC followed by chiral HPLC separation to giveenantiomers 272a and 272b. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.41-7.43(m, 2H), 7.2-6.94 (m, 6H), 4.62 (m, 1H), 4.29 (m, 2H), 4.06 (m, 1H), 3.6(m, 1H), 3.37 (m, 2H), 3.0-2.9 (m, 5H), 1.45 (m, 3H).

Example 183 Preparation of Compound No. 273

To a degassed solution of1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)prop-1-en-2-yltrifluoromethanesulfonate (50 mg, 0.128 mmol) and Pd(PPh₃)₄ (7.4 mg,0.0064) in DME (2 mL) were added potassium carbonate (17.8 mg, 0.1287mmol), water (1 mL) and 1-methyl-1H-pyrazole-5-boronic acid pinacolester (53.5 mg, 0.2574 mmol) and the reaction mixture refluxed for 2.5h. The reaction mixture was cooled to RT, and concentrated to dryness.The residue was extracted into EtOAc, washed with brine, andconcentrated under reduced pressure. ¹H NMR (CD₃OD, TFA salt) δ (ppm):7.40 (d, 1H), 7.21 (s, 1H), 7.15 (m, 2H), 6.87 (d, 1H), 6.38 (s, 1H),4.63 (d, 1H), 4.23 (d, 1H), 3.74 (m, 1H), 3.41 (m, 1H), 3.16 (s, 3H),3.09 (s, 3H), 2.81 (m, 2H), 2.19 (s, 3H), 2.14 (s, 3H).

Example 184 Preparation of Compound Nos. 274 and 274a-b

A solution of1-(4-allyl-2,4,8-trimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-(4-fluoro-phenyl)-propan-2-ol(300 mg, 0.738 mmol) in 6N HCl (10 mL) was stirred at 80° C. for 2 h.The progress of reaction mass was monitored by TLC and LCMS. Thereaction mixture was basified with saturated sodium bicarbonate solutionand extracted with EtOAc (3×25 mL). The combined organic layer was driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby silica gel column chromatography (1% MeOH-DCM) to yield4-allyl-5-[2-(4-fluoro-phenyl)-propenyl]-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.The product is further purified by reverse phase HPLC followed by chiralHPLC separation to give enantiomers 274a and 274b. ¹H NMR (CD₃OD, HClsalt) δ (ppm): 7.62 (m, 2H), 7.27 (s, 1H), 7.20 (m, 2H), 7.04 (m, 3H),6.78-6.82 (m, 1H), 5.18 (d, 2H), 4.78 (d, 1H), 4.37 (d, 1H), 3.58 (m,2H), 3.18 (s, 3H), 2.40 (s, 3H), 2.38 (d, 2H), 1.82 (s, 3H), 1.58 (s,3H).

Example 185 Preparation of Compound No. 275

To a degassed solution of1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg, 0.257 mmol) and Pd(PPh₃)₄ (15 mg,0.0128) in DME (4 mL) were added 1-methylpyrazole-4-boronic acid pinacolester (108 mg, 0.515 mmol), potassium carbonate (36 mg, 0.257 mmol) andwater (2 mL) and the reaction mixture refluxed for 45 min. The reactionmixture was cooled to RT and the solvent was removed under reducedpressure. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.27 (s, 1H), 7.19 (s, 1H),7.04 (d, 1H), 6.98 (d, 1H), 6.46 (m, 2H), 4.78 (d, 1H), 4.39 (d, 1H),3.90 (m, 1H), 3.76 (s, 3H), 3.44 (m, 1H), 3.08 (s, 3H), 2.86 (m, 2H),2.42 (s, 3H), 2.21 (s, 3H).

Example 186 Preparation of Compound No. 276

To a degassed solution of1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg, 0.257 mmol) in DME (4 mL) were addedPd(PPh₃)₄ (15 mg, 0.0128), 2-fluoropyridine-5-boronic acid pinacol ester(115 mg, 0.515 mmol), potassium carbonate (36 mg, 0.257 mmol) and water(2 mL) and the reaction mixture refluxed for 45 min. The reactionmixture was cooled to RT, and the solvent was removed under reducedpressure. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.79 (s, 1H), 7.60 (m, 1H),7.21 (s, 1H), 7.05 (d, 1H), 6.93 (d, 1H), 6.88 (s, 1H), 6.82 (d, 1H),4.62 (d, 1H), 4.25 (d, 1H), 3.78 (m, 1H), 3.42 (m, 1H), 3.13 (s, 3H),2.87 (m, 2H), 2.38 (m, 6H).

Example 187 Preparation of Compound No. 277

To a degassed solution of1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg, 0.257 mmol) in DME (4 mL) were addedPd(PPh₃)₄ (15 mg, 0.0128), 5-methylthiophene-2-boronic acid pinacolester (115 mg, 0.515 mmol), potassium carbonate (36 mg, 0.257 mmol) andwater (2 mL) were added followed by nitrogen purging and water (2 mL)and the reaction mixture refluxed for 45 min. The reaction mixture wascooled to RT, and the solvent was removed under reduced pressure. ¹H NMR(CD₃OD, TFA salt) δ (ppm): 7.25 (s, 1H), 7.13 (d, 1H), 7.0 (d, 1H), 6.82(d, 1H), 6.60 (d, 1H), 6.43 (s, 1H), 4.76 (d, 1H), 4.40 (d, 1H), 3.67(m, 1H), 3.43 (m, 1H), 3.13 (s, 3H), 2.81-2.93 (m, 2H), 2.30 (s, 3H),2.25 (s, 3H), 2.20 (s, 3H).

Example 188 Preparation of Compound No. 278

To a degassed solution of1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg, 0.257 mmol) in DME (4 mL) were addedPd(PPh₃)₄ (15 mg, 0.0128), 5-methylthiophene-2-boronic acid pinacolester (115 mg, 0.515 mmol), potassium carbonate (36 mg, 0.257 mmol) andwater (2 mL) and the reaction mixture refluxed for 45 min. The reactionmixture was cooled to RT, and the solvent was removed under reducedpressure. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.27 (s, 1H), 7.09 (m, 3H),6.98 (s, 1H), 6.79 (s, 1H), 4.78 (d, 1H), 4.40 (d, 1H), 3.87 (m, 1H),3.61 (m, 1H), 3.0-3.20 (m, 5H), 2.45 (s, 3H), 2.40 (s, 3H), 1.89 (s,3H).

Example 189 Preparation of Compound No. 279

To a degassed solution of1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg, 0.257 mmol) in DME (4 mL) were addedPd(PPh₃)₄ (15 mg, 0.0128 mmol), potassium carbonate (36 mg, 0.257 mmol),water (2 mL) and 2-(dimethylamino)pyrimidine-5-boronic acid pinacolester (128 mg, 0.515 mmol). The reaction mixture was refluxed for 45min. At that point, TLC showed no starting material. The reactionmixture was cooled to RT and the solvent evaporated under reducedpressure. The residue was dissolved in EtOAc and filtered through asintered crucible. The filtrate was concentrated and residue purified byreverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.98 (s, 2H), 7.22(s. 1H), 7.08 (d, 1H), 6.99 (d, 1H), 6.80 (s, 1H), 4.65 (d, 1H), 4.31(d, 1H), 3.80 (m, 1H), 3.51 (m, 1H), 3.01-3.81 (m, 11H), 2.40 (s, 3H),2.37 (s, 3H).

Example 190 Preparation of Compound No. 280

To a solution of (4-(1-bromoprop-1-en-2-yl)phenyl)(methyl)sulfane (132mg, 0.55 mmol) in DMF (1 mL) were added potassium phosphate (212 mg, 2mmol), copper(I)iodide (9.5 mg, 0.05 mmol), L-proline (11.5 mg, 0.1mmol) and 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(110 mg, 0.5 mmol) and the reaction mixture stirred at 85° C. for 16 h.Ice water was added into the reaction mixture and the solid obtained wasfiltered. The residue was purified by silica gel column chromatography(0-3% MeOH-DCM) to yield the title compound. ¹H NMR (CD₃OD, oxalatesalt) δ (ppm): 7.58 (m, 3H), 7.37 (d, 2H), 7.21 (s, 2H), 7.0 (s, 1H),4.60 (s, 2H), 3.76 (s, 2H), 3.16 (m, 5H), 2.57 (s, 3H), 1.97 (s, 3H).

Example 191 Preparation of Compound No. 281

To a solution of 1-(1-bromoprop-1-en-2-yl)-4-(methylsulfonyl)benzene(150 mg, 0.55 mmol) in DMF (1 mL) were added potassium phosphate (212mg, 2 mmol), copper(I)iodide (9.5 mg, 0.05 mmol), L-proline (11.5 mg,0.1 mmol) and8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (110 mg, 0.5mmol). The reaction mixture was stirred at 85° C. for 16 h. Ice waterwas added into the reaction mixture and the solid obtained was filtered.The residue was purified by silica gel column chromatography (0-3%MeOH-DCM) to yield the title compound. ¹H NMR (CD₃OD, oxalate salt) δ(ppm): 8.04 (d, 2H), 7.91 (d, 2H), 7.58 (s, 1H), 7.21 (d, 2H), 7.19 (s,1H), 4.57 (s, 2H), 3.70 (s, 2H), 3.15-3.20 (m, 8H), 2.01 (s, 3H).

Example 192 Preparation of Compound No. 282

To a degassed solution of(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg, 0.257 mmol) in DME (4 mL) were addedPd(PPh₃)₄ (15 mg, 0.0128 mmol), potassium carbonate (36 mg, 0.257 mmol),water (2 mL) and 1H-benzimidazole-5-boronic acid pinacol ester (125 mg,0.515 mmol). The reaction mixture was refluxed for 45 min. At thatpoint, TLC showed no starting material. The reaction mixture was cooledto RT and the solvent evaporated under reduced pressure. The residue wasdissolved in EtOAc and filtered through a sintered crucible. Thefiltrate was concentrated and the residue was purified by reverse phaseHPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 9.37 (s, 1H), 8.02 (s, 1H), 7.90(m, 2H), 7.37 (s, 1H), 7.16 (m, 3H), 4.76 (bs, 1H), 4.40 (bs, 1H), 3.90(bs, 1H), 3.60 (bs, 1H), 3.18 (m, 5H), 2.41 (s, 3H), 2.07 (s, 3H).

Example 193 Preparation of Compound No. 283

To a degassed solution of(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg) in DME (4 mL) were added Pd(PPh₃)₄(15 mg), potassium carbonate (36 mg), water (1 mL) and1-methylindole-5-boronic acid pinacol ester (132 mg). The reactionmixture was refluxed for 45 min. At that point, TLC showed no startingmaterial. The reaction mixture was cooled to RT and the solventevaporated under reduced pressure. The residue was dissolved in EtOAcand filtered through a sintered crucible. The filtrate was concentratedand residue was purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt)δ (ppm): 7.80 (d, 1H), 7.42 (d, 1H), 7.39 (d, 1H), 7.31 (s, 1H), 7.20(s, 1H), 7.18 (d, 1H), 7.10 (d, 1H), 6.91 (s, 1H), 6.43 (d, 1H), 4.73(d, 1H), 4.38 (d, 1H), 3.81 (s, 4H), 3.60 (m, 1H), 3.17 (m, 5H), 2.42(s, 3H), 1.98 (s, 3H).

Example 194 Preparation of Compound No. 284

To a degassed solution of(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg) in DME (4 mL) were added Pd(PPh₃)₄(15 mg), potassium carbonate (36 mg), water (1 mL) and1-methylindole-5-boronic acid pinacol ester (132 mg). The reactionmixture was refluxed for 45 min. At that point, TLC showed no startingmaterial. The reaction mixture was cooled to RT and the solvent removedunder reduced pressure. The residue was dissolved in EtOAc and filteredthrough a sintered crucible. The filtrate was concentrated and residuepurified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.31(d, 2H), 7.20 (s, 1H), 7.05 (m, 3H), 6.80 (d, 1H), 6.76 (s, 1H), 6.21(d, 1H), 4.51 (d, 1H), 4.20 (d, 1H), 3.70 (s, 3H), 3.52 (m, 2H), 3.19(m, 2H), 2.80 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H).

Example 195 Preparation of Compound No. 285

To a degassed solution of[(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate] (100 mg, 0.257 mmol) in DME (4 mL) were addedPd(PPh₃)₄ (15 mg, 0.0128 mmol), potassium carbonate (36 mg, 0.257 mmol),water (2 mL) and 4-methylthiophene-2-boronic acid pinacol ester (115 mg,0.515 mmol). The reaction mixture was refluxed for 45 min. At thatpoint, TLC showed no starting material. The reaction mixture was cooledto RT and the solvent evaporated under reduced pressure. The residue wasdissolved in EtOAc and filtered through a sintered crucible. Thefiltrate was concentrated under vacuum and the residue was purified byreverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.30 (s, 1H), 7.18(s, 1H), 7.05 (m, 3H), 6.98 (s, 1H), 4.71 (d, 1H), 4.40 (d, 1H), 3.82(m, 1H), 3.57 (m, 1H), 3.18 (m, 2H), 3.10 (s, 3H), 2.41 (s, 3H), 2.23(s, 3H), 1.87 (s, 3H).

Example 196 Preparation of Compound No. 286

To a degassed solution of[(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate] (100 mg, 0.257 mmol) in DME (4 mL) were addedP(PPh₃)₄ (15 mg, 0.0128 mmol), potassium carbonate (36 mg, 0.257 mmol),water (2 mL) and naphthalene-1-boronic acid (88 mg, 0.515 mmol). Thereaction mixture was refluxed for 45 min. At that point, TLC showed nostarting material. The reaction mixture was cooled to RT and the solventevaporated under reduced pressure. The residue was dissolved in EtOAcand filtered through a sintered crucible. The filtrate was concentratedand product isolated by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 7.92 (d, 1H), 7.78 (d, 1H), 7.67 (m, 1H), 7.29-7.41 (m, 5H), 7.13(s, 1H), 7.0 (s, 1H), 6.98 (d, 1H), 4.40 (d, 1H), 4.11 (d, 1H), 3.51 (m,1H), 3.21 (m, 1H), 2.80 (s, 3H), 2.71 (m, 2H), 2.42 (s, 3H), 2.37 (s,3H).

Example 197 Preparation of Compound No. 287

To a solution of[(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate] (100 mg, 0.257 mmol) in DME (4 mL) was addedPd(PPh₃)₄ (15 mg, 0.0128 mmol) and solution purged with nitrogen for 5min. Potassium carbonate (36 mg, 0.257 mmol), water (2 mL) and3-methylthiophene-2-boronic acid pinacol ester (115 mg, 0.515 mmol) wereadded followed by nitrogen purging. The reaction mixture was refluxedfor 45 min. At that point, TLC showed no starting material. The reactionmixture was cooled to RT and the solvent evaporated under reducedpressure. The residue was dissolved in EtOAc and filtered through asintered crucible. The filtrate was concentrated under reduced pressureand residue purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 7.21 (d, 1H), 7.19 (s, 1H), 7.12 (d, 1H), 6.96 (d, 1H), 6.82 (s,1H), 6.61 (d, 1H), 4.60 (d, 1H), 4.23 (d, 1H), 3.68 (m, 1H), 3.40 (m,1H), 3.0 (s, 3H), 2.80 (m, 2H), 2.40 (s, 3H), 2.37 (s, 3H), 1.58 (s,3H).

Example 198 Preparation of Compound Nos. 288 and 288a-b

A solution of5-(2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indoleand5-(2-(4-fluorophenyl)allyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(1.8 g, 5.38 mmol) and 10% Pd/C (180 mg) in MeOH-acetic acid (50 mL,10:1) was hydrogenated in a Parr shaker at RT and 60 psi for 18 h. Thereaction mixture was filtered through a Celite bed and the filtrateconcentrated under reduced pressure. The residue was diluted with EtOAc(500 mL) and washed with satd. sodium bicarbonate solution (50 mL) andthen brine. The organic layer was dried over anhydrous sodium sulfateconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (0 to 50% EtOAc in hexanes) to yield the titlecompound. ¹HNMR (DMSO, Oxalate salt) δ (ppm):7.38-7.3 (d, 1H), 7.36 (bs,1H), 7.19 (s, 2H), 7.07 (bs, 2H), 6.97-6.95 (d, 1H), 4.53 (m, 1H),4.24-4.12 (m, 3H), 3.86 (m, 1H), 3.25 (m, 1H), 3.06 (m, 1H), 2.98 (s,3H), 2.78 (bs, 1H), 2.62 (bs, 1H), 2.33 (s, 3H), 1.14 (bs, 3H).Separation by chiral HPLC provided enantiomers 288a-b.

Example 199 Preparation of Compound Nos. 289 and 289a-b

A solution of2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)prop-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg) and 10% Pd/C (20 mg) in MeOH (5 mL) was hydrogenated in a Parrshaker at RT and 50 psi for 72 h. The progress of reaction was monitoredby LCMS. The reaction mass was filtered through a Celite bed and thefiltrate concentrated under reduced pressure. The residue was purifiedby reverse phase HPLC to yield the title compound. ¹HNMR (CD₃OD, TFAsalt) δ (ppm): 8.30 (m, 2H), 7.70 (s, 1H), 7.20 (s, 1H), 7.10 (d, 1H),6.98 (d, 1H), 4.60 (m, 2H), 4.30 (m, 3H), 3.80 (m, 2H), 3.60 (m, 2H),3.10 (s, 3H), 2.62 (s, 3H), 2.38 (s, 3H), 1.42 (d, 3H). Separation bychiral HPLC provided enantiomers 289a-b.

Example 200 Preparation of Compound No. 290

To a solution of[(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate] (100 mg, 0.257 mmol) in DME (4 mL) was addedPd(PPh₃)₄ (15 mg, 0.0128 mmol) and solution purged with nitrogen for 5min. Potassium carbonate (72 mg, 0.515 mmol), water (2 mL) andindazole-4-boronic acid.HCl (102 mg, 0.515 mmol) were added followed bynitrogen purging. The reaction mixture was refluxed for 45 min. At thatpoint, TLC showed no starting material. The reaction mixture was cooledto RT and the solvent evaporated under reduced pressure. The residue wasdissolved in EtOAc and filtered through a sintered crucible. Thefiltrate was concentrated under vacuum and the product isolated byreverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.57 (s, 1H), 7.40(d, 1H), 7.31 (m, 2H), 7.12 (s, 1H), 7.05 (d, 1H), 7.0 (s, 2H), 4.51 (d,1H), 4.17 (d, 1H), 3.58 (m, 1H), 3.21 (m, 1H), 2.81 (s, 3H), 2.60 (m,2H), 2.41 (s, 3H), 2.38 (s, 3H).

Example 201 Preparation of Compound No. 291

To a solution of[(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate] (100 mg, 0.257 mmol) in DME (4 mL) was addedPd(PPh₃)₄ (15 mg, 0.0128 mmol) and solution purged with nitrogen for 5min. Potassium carbonate (36 mg, 0.257 mmol), water (2 mL) and4-methylthiophene-2-boronic acid pinacol ester (115 mg, 0.515 mmol) wereadded followed by nitrogen purging. The reaction mixture was refluxedfor 45 min. At that point, TLC showed no starting material. The reactionmixture was cooled to RT and the solvent evaporated under reducedpressure. The residue was dissolved in EtOAc and filtered through asintered crucible. The filtrate was concentrated under vacuum and theproduct isolated by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 7.23 (s, 1H), 7.08 (d, 1H), 7.00 (d, 1H), 6.85 (s, 1H), 6.78 (s,1H), 6.55 (s, 1H), 4.73 (d, 1H), 4.38 (d, 1H), 3.71 (m, 1H), 3.42 (m,1H), 3.05 (s, 3H), 2.97 (m, 1H), 2.80 (m, 1H), 2.42 (s, 3H), 2.38 (s,3H), 2.20 (s, 3H).

Example 202 Preparation of Compound No. 292

To a degassed solution of(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg, 0.257 mmol) in DME (2 mL) were addedPd(PPh₃)₄ (20 mg, 0.017 mmol), potassium carbonate (110 mg, 0.77 mmol),water (1 mL) and isoquinoline-4-boronic acid (89 mg, 0.515 mmol). Thereaction mixture was refluxed for 45 min. At that point, TLC showed nostarting material. The reaction mixture was cooled to RT and dilutedwith EtOAc. The aqueous layer was extracted with EtOAc (3×6 mL) and thecombined organic layer was dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and residue was purified byreverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 9.8 (s, 1H), 8.78(s, 1H), 8.6 (d, 1H), 8.46 (d, 1H), 8.38 (dd, 1H), 8.17 (dd, 1H), 7.4(m, 2H), 7.2 (d, 1H), 7.02 (s, 1H), 4.8 (d, 1H), 4.41 (d, 1H), 3.82 (m,1H), 3.62 (m, 1H), 3.36 (m, 2H), 3.19 (s, 3H), 2.41 (s, 3H), 2.18 (s,3H).

Example 203 Preparation of Compound No. 293

To a degassed solution of(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg, 0.257 mmol) and potassium carbonate(110 mg, 0.796 mmol), in DME (2 mL)-water (1 mL) were added Pd(PPh₃)₄(20 mg, 0.017 mmol) and thianaphthene-2-boronic acid (91.4 mg, 0.514mmol) followed by nitrogen purging. The reaction mixture was refluxedfor 45 min. At that point, TLC showed no starting material. The reactionmixture was cooled to RT and diluted with EtOAc. The aqueous layer wasextracted with EtOAc (3×6 mL) and the combined organic layer dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureto afford crude product which was purified by reverse phase HPLC. ¹H NMR(CD₃OD, TFA salt) δ (ppm): 7.78 (d, 1H), 7.52 (d, 1H), 7.5 (s, 1H), 7.32(s, 1H), 7.2-7.3 (m, 2H), 7.18 (d, 1H), 7.03 (d, 1H), 6.78 (s, 1H), 4.7(d, 1H), 4.4 (d, 1H), 3.7 (m, 1H), 3.43 (m, 1H), 3.08 (s, 3H), 2.8 (m,2H), 2.49 (s, 3H), 2.41 (s, 3H).

Example 204 Preparation of Compound No. 294

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(200 mg, 1.0 mmol) in NMP (1 mL) were added powdered KOH (392 mg, 7.0mmol) and 3-vinyl-benzo[b]thiophene (320 mg, 2.0 mmol). The reactionmixture was stirred at 90° C. for 5 h. The reaction mixture was dilutedwith water (15 mL) and extracted with EtOAc (3×20 mL). The combinedorganic layer was washed with water (5×25 mL), dried over anhydroussodium sulfate and concentrated. The residue was purified by silica gelcolumn chromatography (3% MeOH-DCM) followed by reverse phase HPLC toyield5-(2-benzo[b]thiophen-3-yl-ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CDCl₃, freebase) δ (ppm): 7.82 (d, 1H), 7.6 (d, 1H), 7.38 (m,2H), 7.2 (m, 2H), 7.0 (d, 1H), 6.93 (s, 1H), 4.3 (t, 2H), 3.62 (s, 2H),3.5 (s, 3H), 3.21 (t, 2H), 2.63 (t, 2H), 2.41 (m, 5H).

Example 205 Preparation of Compound No. 295

To a solution of 3-(1-bromoprop-1-en-2-yl)phenyl)(methyl)sulfane (300mg, 1.2 mmol) in DMF (2 mL) were added potassium phosphate (424 mg, 2mmol), copper(I)iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol)and 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (220 mg,1 mmol). The reaction mixture was stirred at 140° C. for 16 h. Ice waterwas added to the reaction mixture and extracted with EtOAc (3×15 mL).The combined organic layer was washed with water (2×10 mL), dried andconcentrated. The residue was purified by silica gel columnchromatography (0-3% MeOH-DCM) followed by reverse phase HPLC to yieldthe title compound. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.57 (d, 1H), 7.5(d, 1H), 7.38-7.42 (m, 2H), 7.3 (d, 1H), 7.2 (m, 2H), 6.97 (s, 1H), 4.7(d, 1H), 4.4 (d, 1H), 3.82 (m, 1H), 3.6 (m, 1H), 3.1 (m, 5H), 2.5 (s,3H), 1.98 (s, 3H).

Example 206 Preparation of Compound No. 296

To a solution of 1-(1-bromoprop-1-en-2-yl)-3-(methylsulfonyl)benzene(297 mg, 1.1 mmol) in DMF (2 mL) were added potassium phosphate (424 mg,2 mmol), copper(I)iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol)and 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (220 mg,1 mmol) and purged nitrogen for 2 min and heated at 90° C. for 16 h. Icewater (5 mL) was added and filtered the solid obtained and washed withwater (2×10 mL). Product was purified on silica column (100-200 mesh)using 0-3% MeOH:DCM as eluant. The compound was further purified throughreverse phase HPLC. Yield: 49.26 mg (freebase). ¹H NMR (CD₃OD, freebase)δ (ppm): 8.2 (s, 1H), 7.98 (m, 2H), 7.7 (dd, 1H), 7.48 (s, 1H), 7.18 (m,2H), 7.1 (s, 1H), 4.2 (s, 2H), 3.4 (s, 2H), 3.2 (s, 3H), 3.1 (s, 2H),2.9 (s, 3H), 1.8 (s, 3H).

Example 207 Preparation of Compound No. 297

To a degassed stirred solution of2,8-dimethyl-5-(6-methyl-pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.317 mmol) in MeOH (5 mL) was added Pd/C (35 mg, 35% w/w) andpurged the reaction mixture with H₂ gas at RT for 2 h. The progress ofreaction was monitored by TLC and NMR. Reaction mass was filteredthrough a Celite bed washed with MeOH (3×5 mL). Filtrate wasconcentrated under reduced pressure and residue was purified by reversephase HPLC to yield2,8-dimethyl-5-[2-(6-methyl-pyridin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.2 (dd, 1H), 7.63 (d, 1H), 7.57 (d,1H), 7.21 (d, 1H), 7.02 (d, 1H), 6.96 (d, 1H), 4.7 (d, 1H), 4.58 (t,2H), 4.37 (d, 1H), 3.82 (m, 1H), 3.57 (m, 1H), 3.4 (t, 2H), 3.2 (m, 2H),3.18 (s, 3H), 2.61 (s, 3H), 2.4 (s, 3H).

Example 208 Preparation of Compound No. 298

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.5 mmol) was in NMP (1 mL) were added powdered KOH (196 mg,3.5 mmol) and dimethyl-(3-vinyl-phenyl)-amine (147 mg, 1.0 mmol) and thereaction mixture stirred at 100° C. for 16 h. The progress of reactionwas monitored by TLC and LCMS. The reaction mixture was diluted withwater (15 mL) and extracted with EtOAc (3×25 mL). The combined organiclayer was washed with water (5×20 mL), dried over anhydrous sodiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (0-3% MeOH-DCM) to yield{3-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-phenyl}-dimethyl-amine.¹H NMR (CDCl₃, freebase) δ (ppm): 7.21 (m, 2H), 7.18 (dd, 1H), 7.0 (d,1H), 6.6 (d, 1H), 6.43 (d, 1H), 6.21 (s, 1H), 4.2 (t, 2H), 3.71 (s, 2H),2.90 (t, 2H), 2.85 (s, 3H), 2.80 (m, 4H), 2.57 (s, 6H), 2.41 (s, 3H).

Example 209 Preparation of Compound No. 299

To a degassed stirred solution of2,8-dimethyl-5-(5-methyl-pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(110 mg, 0.349 mmol) in MeOH (5 mL) was added Pd/C (40 mg, 35% w/w) andpurged the reaction mixture with H₂ gas at RT for 2 h. The progress ofreaction was monitored by TLC and NMR. Reaction mass was filteredthrough a Celite bed washed with MeOH (3×5 mL). Filtrate wasconcentrated under reduced pressure and residue was purified by reversephase HPLC to yield2,8-dimethyl-5-[2-(5-methyl-pyridin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.42 (s, 1H), 8.02 (d, 1H), 7.48 (d,1H), 7.21 (s, 1H), 7.12 (d, 1H), 6.98 (d, 1H), 4.67 (d, 1H), 4.5 (t,2H), 4.3 (d, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.38 (t, 2H), 3.1 (m, 5H),2.41 (s, 3H), 2.39 (s, 3H).

Example 210 Preparation of Compound No. 300

To a degassed stirred solution of5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.29 mmol), 3-pyridinylboronic acid (71 mg, 0.577 mmol) andpotassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4mL)-water (2 mL) was added Pd(PPh₃)₄ (16 mg, 0.0147 mmol). The reactionmixture was stirred at 90° C. for 45 min. The reaction mixtureconcentrated, residue diluted with water (20 mL) and extracted withEtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified byreverse phase HPLC to yield2,8-dimethyl-5-(2-(pyridin-3-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.68 (d, 1H), 8.1 (d, 1H), 7.9 (m,1H), 7.8 (m, 1H), 7.3 (s, 1H), 6.9-7.1 (m, 2H), 4.7 (m, 1H), 4.4 (m,1H), 3.8 (m, 1H), 3.58 (m, 1H), 2.8-3.3 (m, 9H), 2.22-2.4 (m, 5H).

Example 211 Preparation of Compound No. 301

To a degassed stirred solution of5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.29 mmol), 4-fluorophenylboronic acid (81 mg, 0.578 mmol) andpotassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4mL)-water (2 mL) was added Pd(PPh₃)₄ (17 mg, 0.0147 mmol). The reactionmixture was stirred at 90° C. for 45 min. The reaction mixtureconcentrated to dryness, residue diluted with water (20 mL) andextracted with EtOAc (50 mL). The organic layer was dried over anhydroussodium sulfate, concentrated under reduced pressure. The residue waspurified by reverse phase HPLC to yield5-(2-(4-fluorophenyl)cyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.3 (s, 1H), 7.17 (d, 1H), 7.02 (d,1H), 6.8-6.98 (m, 4H), 4.7 (d, 1H), 4.3 (d, 1H), 3.65 (m, 1H), 3.41 (m,1H), 2.9-3.18 (m, 7H), 2.52-2.77 (m, 2H), 2.45 (s, 3H), 2.21 (m, 2H).

Example 212 Preparation of Compound No. 302

To a degassed stirred solution of5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.29 mmol), 3-methylthiophene-2-boronic acid pinacol ester (129mg, 0.575 mmol) and potassium carbonate (120 mg, 0.87 mmol) in1,2-dimethoxyethane (4 mL)-water (2 mL) was added Pd(PPh₃)₄ (16 mg,0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. Thesolvent was under reduced pressure, residue diluted with water (20 mL)and extracted with EtOAc (50 mL). The organic layer was dried overanhydrous sodium sulfate and concentrated. The residue was purified byreverse phase HPLC to yield2,8-dimethyl-5-(2-(3-methylthiophen-2-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.24 (s, 1H), 7.1-7.2 (m, 2H), 7.0(dd, 1H), 6.6 (s, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 3.64 (m, 1H), 3.2 (m,1H), 2.8-3.17 (m, 7H), 2.6 (t, 2H), 2.4 (s, 3H), 2.2 (t, 2H), 1.8 (m,3H).

Example 213 Preparation of Compound No. 303

To a degassed stirred solution of5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.29 mmol), 2-(dimethylamino)pyrimidine-5-boronic acid pinacolester (129 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol)in 1,2-dimethoxyethane (4 mL)-water (2 mL) was added Pd(PPh₃)₄ (16 mg,0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. Thesolvent was removed under reduced pressure, residue diluted with water(20 mL) and extracted with EtOAc (50 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby reverse phase HPLC to yield5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)cyclopent-1-enyl)-N,N-dimethylpyrimidin-2-amine.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.8 (d, 2H), 7.3 (s, 1H), 6.98-7.1 (m,2H), 4.7 (m, 1H), 4.38 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 2.78-3.1 (m,15H), 2.4 (s, 3H), 2.2 (m, 2H).

Example 214 Preparation of Compound No. 304

To a degassed stirred solution of5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.29 mmol), 4-methylthiophene-2-boronic acid pinacol ester (129mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in1,2-dimethoxyethane (4 mL)-water (2 mL) was purged with nitrogenfollowed by addition of Pd(PPh₃)₄ (16 mg, 0.0147 mmol). The reactionmixture was stirred at 90° C. for 45 min. The solvent was removed underreduced pressure, residue diluted with water (20 mL) and extracted withEtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfateand concentrated. The residue was purified by reverse phase HPLC toyield2,8-dimethyl-5-(2-(4-methylthiophen-2-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.3 (s, 1H), 7.0 (m, 3H), 6.78 (s,1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.37 (s, 3H),3.03 (m, 2H), 2.83 (m, 2H), 2.61 (m, 2H), 2.4 (s, 3H), 2.2 (m, 2H), 2.17(s, 3H).

Example 215 Preparation of Compound No. 305

A solution of5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.29 mmol), benzo[b]thien-2-ylboronic acid (103 mg, 0.578 mmol)and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4mL)-water (2 mL) was purged with nitrogen followed by addition ofPd(PPh₃)₄ (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90°C. for 45 min. The solvent was removed under reduced pressure, residuediluted with water (20 mL) and extracted with EtOAc (50 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by reverse phase HPLC to yield5-(2-(benzo[b]thiophen-2-yl)cyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.2 (d, 1H), 7.5 (d, 1H), 7.38 (s,1H), 7.2-7.3 (m, 3H), 7.1 (d, 1H), 7.04 (d, 1H), 4.4 (m, 2H), 3.6 (m,2H), 3.2 (m, 2H), 3.1 (s, 3H), 2.9 (m, 2H), 2.7 (m, 2H), 2.41 (s, 3H),2.3 m, 2H).

Example 216 Preparation of Compound No. 306

A solution of5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.29 mmol), naphthalene-1-boronic acid (99 mg, 0.575 mmol) andpotassium carbonate (120 mg, 0.87 mmol) in mixture of1,2-dimethoxyethane (4 mL)-water (2 mL) was purged with nitrogenfollowed by addition of Pd(PPh₃)₄ (16 mg, 0.0147 mmol). The reactionmixture was stirred at 90° C. for 45 min. The solvent was removed underreduced pressure, residue diluted with water (20 mL) and extracted withEtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfateand concentrated. The residue was purified by reverse phase HPLC toyield2,8-dimethyl-5-(2-(naphthalen-1-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (DMSO, TFA salt) δ (ppm): 8.0 (d, 1H), 7.8 (d, 1H), 7.79 (d, 1H),7.3-7.5 (m, 5H), 7.1 (s, 1H), 6.9 (d, 1H), 4.21 (m, 2H), 3.4 (m, 2H),2.77-3.0 (m, 9H), 2.3 (m, 5H).

Example 217 Preparation of Compound No. 307

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(150 mg, 0.75 mmol) in NMP (1 mL) were added powdered KOH (294 mg, 5.25mmol) and 2-methyl-5-vinyl-thiophene (186 mg, 1.50 mmol), and thereaction mixture stirred at 90° C. for 5 h. The reaction mixture wasdiluted with water (15 mL) and extracted with EtOAc (3×20 mL). Thecombined organic layer was washed with water (5×25 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (3% MeOH-DCM)followed by reverse phase HPLC to yield2,8-dimethyl-5-[2-(5-methyl-thiophen-2-yl)-ethyl]-2,5-dihydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.3 (d, 1H), 7.22 (s, 1H), 7.08 (d,1H), 6.5 (d, 1H), 6.3 (d, 1H), 4.6 (d, 1H), 4.2-4.4 (m, 3H), 3.7 (m,2H), 3.2 (m, 3H), 3.03 (s, 3H), 2.7 (m, 1H), 2.38-2.42 (m, 6H).

Example 218 Preparation of Compound No. 308

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(250 mg, 1.25 mmol) in NMP (1 mL) were added powdered KOH (490 mg, 8.75mmol) and 3-methyl-2-vinyl-thiophene (310 mg, 2.25 mmol), and thereaction mixture stirred at 90° C. for 5 h. The reaction mixture wasdiluted with water (20 mL) and extracted with EtOAc (3×20 mL). Thecombined organic layer was washed with water (5×25 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by reverse phase HPLC to yield2,8-dimethyl-5-[2-(3-methyl-thiophen-2-yl)-ethyl]-2,5-dihydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.25 (d, 1H), 7.22 (s, 1H), 7.1 (d,1H), 7.02 (d, 1H), 6.7 (d, 1H), 4.41 (s, 2H), 4.3 (t, 2H), 2.42 (bs,2H), 3.2 (t, 2H), 3.0 (s, 3H), 2.61 (bs, 2H), 2.4 (s, 3H), 1.6 (s, 3H).

Example 219 Preparation of Compound No. 309

To a degassed stirred solution of5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.29 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester(81 mg, 0.576 mmol) and potassium carbonate (120 mg, 0.87 mmol) in1,2-dimethoxyethane (4 mL) and water (2 mL) was added Pd(PPh₃)₄ (17 mg,0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. Thesolvent was removed under reduced pressure, residue diluted with water(20 mL) and extracted with EtOAc (50 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby reverse HPLC to yield2,8-dimethyl-5-(2-(1-methyl-1H-pyrazol-5-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CDCl₃, freebase) δ (ppm): 7.32 (s, 1H), 7.18 (s, 1H), 7.0 (d,1H), 6.9 (d, 1H), 6.01 (s, 1H), 3.6 (s, 2H), 3.2 (s, 3H), 3.0 (m, 4H),2.7 (m, 4H), 2.52 (s, 3H), 2.4 (s, 3H), 2.2 (m, 2H).

Example 220 Preparation of Compound No. 310

To a solution of 1-(1-bromoprop-1-en-2-yl)-3-(methylsulfonyl)benzene(148 mg, 0.55 mmol) in DMF (1 mL) were added potassium phosphate (212mg, 2 mmol), copper(I)iodide (9.5 mg, 0.05 mmol) and L-proline (11.5 mg,0.1 mmol). The solution was de-aerated by purging nitrogen followed byaddition of 2,3,4,5-tetrahydro-2,6,8-trimethyl-1H-pyrido[4,3-b]indole(114.5 mg, 0.5 mmol). The reaction mixture was again purged withnitrogen for two minutes and then stirred at 85° C. overnight. Ice waterwas poured into the reaction mixture and the solid obtained wasfiltered. The crude product was purified by column chromatography using0-3% MeOH:DCM as eluant. The compound was further purified throughreverse phase HPLC to yield the title compound. ¹H NMR (CD₃OD, TFA salt)δ (ppm): 8.08 (s, 1H), 8.0 (m, 2H), 7.77 (t, 1H), 7.38 (s, 1H), 7.1 (s,1H), 6.8 (s, 1H), 4.7 (d, 1H), 4.37 (d, 1H), 3.82 (m, 1H), 3.58 (m, 1H),3.0-3.2 (m, 8H), 2.73 (s, 3H), 2.38 (s, 3H), 1.97 (s, 3H).

Example 221 Preparation of Compound No. 311

To a degassed solution of(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate (100 mg, 0.257 mmol) and potassium carbonate(110 mg, 0.7 mmol) in DME-water (2:1) were added Pd(PPh₃)₄ (20 mg,0.0130 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (100 mg,0.392 mmol), followed by nitrogen purging for 5 min. The reactionmixture was refluxed for 45 min. At that point, TLC showed no startingmaterial. The reaction mixture was cooled to RT and extracted withEtOAc. The combined organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 9.77(s, 1H), 8.6 (d, 1H), 8.44-8.58 (m, 3H), 8.4 (d, 1H), 7.57 (s, 1H), 7.37(s, 1H), 7.2 (d, 1H), 7.17 (d, 1H), 4.71 (d, 1H), 4.4 (d, 1H), 3.9 (m,1H), 3.6 (m, 1H), 3.2 (m, 5H), 2.42 (s, 3H), 2.2 (s, 3H).

Example 222 Preparation of Compound No. 312

To a solution of 4-(1-bromoprop-1-en-2-yl)pyridine (238 mg, 1.2 mmol) inDMF (2 mL) were added potassium phosphate (424 mg, 2 mmol),copper(I)iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and2,3,4,5-tetrahydro-2,6,8-trimethyl-1H-pyrido[4,3-b]indole (214 mg, 1mmol). The reaction mixture was degassed using nitrogen and stirredovernight at 85° C. Ice water (5 mL) was added into the reaction mixtureand the solid obtained was filtered. The residue was washed with water(2×10 mL) and purified by column chromatography using neutral aluminaand 0-1% MeOH:DCM as eluant to yield the desired compound. ¹H NMR(CD₃OD, HCl salt) δ (ppm): 8.9 (d, 2H), 8.39 (d, 2H), 7.98 (s, 1H), 7.17(s, 1H), 6.86 (s, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.82 (m, 1H), 3.6 (m,1H), 3.2 (m, 4H), 3.0 (m, 1H), 2.5 (s, 3H), 2.4 (s, 3H), 2.1 (s, 3H).

Example 223 Preparation of Compound No. 313

A mixture of5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (194mg, 0.866 mmol, 5-bromo-isoquinoline (150 mg, 0.721 mmol, TBAF.3H₂O (680mg, 2.15 mmol) and dichlorobis(triphenylphosphine) palladium(II) (25 mg,0.035 mmol) was stirred at 85° C. for 5 min. The reaction mixture wasdiluted with water and extracted with EtOAc (3×40 mL). The organic layerwas washed with water (5×30 mL), dried over anhydrous sodium sulfate andconcentrated. The crude product was purified by column chromatographyusing silica (100:200) and 0.5% MeOH-DCM to yield5-isoquinolin-5-ylethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CDCl₃, freebase) δ (ppm): 9.3 (s, 1H), 8.62 (d, 1H), 8.17 (d,1H), 7.93 (dd, 2H), 7.6 (t, 1H), 7.57 (d, 1H), 7.23 (s, 1H), 7.17 (d,1H), 3.65 (s, 2H), 3.07 (t, 2H), 2.93 (t, 2H), 2.6 (s, 3H), 2.42 (s,3H).

Example 224 Preparation of Compound Nos. 314 and 314a-b

To a solution of2,3,4,9-tetrahydro-2,6-dimethyl-1-phenyl-1H-pyrido[3,4-b]indole (100 mg,0.362 mmol) in DMF (2 mL) were added sodium hydride (60 mg, 1.08 mmol)and 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (300 mg, 1.03mmol). The reaction mixture was irradiated in a microwave reactor at 90°C. for 1 h. The reaction mixture was cooled to RT and quenched withwater. The aqueous layer was extracted with EtOAc (3×10 mL). The organiclayer was washed with water (2×10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford crude product,which was purified by reverse phase HPLC. The product is furtherpurified by reverse phase HPLC followed by chiral HPLC separation togive enantiomers 314a and 314b. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.09(s, 1H), 7.9 (d, 1H), 7.63 (t, 1H), 7.43-7.6 (m, 5H), 7.4 (s, 1H), 7.0(m, 2H), 6.03 (s, 1H), 4.37 (t, 1H), 4.1 (m, 1H), 3.92 (m, 1H),3.57-3.65 (m, 2H), 3.18 (t, 1H), 2.9 (bs, 3H), 2.63 (s, 3H), 2.6 (m,2H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers 314a-b.

Example 225 Preparation of Compound No. 315

To a solution of7-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg,0.453 mmol) in DMF (2 mL) were added sodium hydride (60 mg, 1.359 mmol)and 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (330 mg,1.1322 mmol). The reaction mixture was irradiated in a microwave reactorat 90° C. for 1 h. The reaction mixture was cooled to RT and quenchedwith water. The aqueous layer was extracted with EtOAc (3×10 mL). Theorganic layer was washed with water (2×10 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to afford crudeproduct, which was purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFAsalt) δ (ppm): 8.21 (s, 1H), 8.1 (d, 1H), 7.7 (d, 1H), 7.38 (d, 1H), 7.1(s, 1H), 7.0 (d, 1H), 4.7 (d, 1H), 4.42 (t, 2H), 4.5 (d, 1H), 3.82 (m,1H), 3.57 (m, 1H), 3.1-3.27 (m, 4H), 3.08 (s, 3H), 2.63 (s, 3H).

Example 226 Preparation of Compound No. 316

To a solution of5-isoquinolin-5-ylethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(90 mg, 0.256 mmol) in MeOH (6 mL) were added 10% dry Pd—C (25 mg) andammonium formate (81 mg, 1.282 mmol). The reaction mixture was refluxedfor 2 h and filtered through Celite. The filtrate was concentrated underreduced pressure to afford crude product, which was purified by reversephase HPLC to yield 20 mg of5-(2-isoquinolin-5-yl-vinyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 9.7 (s, 1H), 8.57 (d, 1H), 8.5 (d,1H), 8.3 (d, 1H), 7.65 (t, 1H), 7.59 (d, 1H), 7.4 (d, 1H), 7.22 (d, 1H),7.2 (s, 1H), 6.7 (m, 2H), 4.63 (d, 1H), 4.3 (d, 1H), 3.7 (m, 1H), 3.47(m, 1H), 3.08 (s, 3H), 2.9-3.0 (m, 2H), 2.31 (s, 3H).

Example 227 Preparation of Compound No. 317

To a solution of5-isoquinolin-5-ylethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(80 mg, 0.228 mmol) in MeOH (5 mL) were added 10% dry Pd—C (80 mg) andammonium formate (72 mg, 1.14 mmol). The reaction mixture was refluxedfor 4 h and filtered through Celite. The filtrate was concentrated underreduced pressure to afford crude product, which was purified by reversephase HPLC to yield 20 mg of2,8-dimethyl-5-[2-(1,2,3,4-tetrahydro-isoquinolin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.21 (d, 1H), 7.18 (m, 2H), 7.1 (d,1H), 7.0 (d, 1H), 6.93 (d, 1H), 4.7 (d, 1H), 4.2-4.4 (m, 5H), 3.7 (m,1H), 3.2 (m, 3H), 3.08 (t, 2H), 3.02 (s, 3H), 2.83 (m, 1H), 2.6-2.8 (m,3H), 2.4 (s, 3H).

Example 228 Preparation of Compound No. 318

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(250 mg, 1.255 mmol) in NMP (1 mL), was added powdered KOH (490 mg, 8.75mmol). After stirring for 5 min, 3-methyl-4-vinyl-thiophene (310 mg,2.50 mmol) was added into the reaction mixture, which was stirred at 85°C. for 16 h. The reaction mixture was diluted with water (15 mL) andextracted with EtOAc (3×20 mL). The organic layer was washed with water(6×30 mL), dried over anhydrous sodium sulfate and concentrated. Thecrude product was purified by column chromatography using silica(100:200) and 2% MeOH-DCM, followed by reverse phase HPLC to yield 1.10mg of2,8-dimethyl-5-[2-(4-methyl-thiophen-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.3 (d, 1H), 7.24 (s, 1H), 7.07 (d,1H), 6.92 (s, 1H), 6.78 (s, 1H), 4.6 (d, 1H), 4.3 (m, 3H), 3.62 (m, 1H),3.3 (m, 3H), 3.0 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H), 1.95 (s, 3H).

Example 229 Preparation of Compound No. 319

To a solution of8,9-dichloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (100 mg,0.392 mmol) in DMF (2 mL) were added sodium hydride (60 mg, 1.17 mmol)and 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (300 mg, 0.98mmol). The reaction mixture was irradiated in a microwave reactor at 90°C. for 1 h. The reaction mixture was cooled to RT and quenched withwater. The aqueous layer was extracted with EtOAc (3×10 mL). The organiclayer was washed with water (2×10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford crude product,which was purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 8.39 (s, 1H), 8.2 (d, 1H), 7.7 (d, 1H), 7.2 (d, 2H), 5.1 (m, 1H),4.6 (m, 1H), 4.43 (t, 2H), 3.82 (m, 1H), 3.5 (m, 1H), 3.2-3.3 (m, 4H),3.1 (m, 3H), 2.7 (s, 3H).

Example 230 Preparation of Compound No. 320

To a degassed solution of2,8-dimethyl-5-quinolin-3-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(60 mg, 0.170 mmol) in MeOH (5 mL), were added Pd—C (30 mg, 50% w/w) andammonium formate (54 mg, 0.857 mmol) under nitrogen. The reactionmixture was stirred at 75° C. for 1 h, filtered through a Celite bed andwashed with MeOH (10 mL). The filtrate was concentrated under reducedpressure and residue was purified by reverse phase HPLC to yield thedesired compound. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.6 (s, 2H),8.02-8.18 (m, 3H), 7.82 (t, 1H), 7.2 (s, 1H), 6.98 (d, 1H), 6.77 (d,1H), 4.68 (d, 1H), 4.56 (t, 2H), 4.3 (d, 1H), 3.8 (m, 1H), 3.45 (m, 1H),3.4 (t, 2H), 3.21 (m, 1H), 3.1 (m, 4H), 2.3 (s, 3H).

Example 231 Preparation of Compound No. 321

A mixture of5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (260mg, 1.160 mmol), 3-bromoquinoline (200 mg, 0.961 mmol), TBAF.3H₂O (1.1g, 3.492 mmol) and dichloro bis(triphenylphosphine) palladium (II) (41mg, 0.058 mmol) was stirred at 85° C. for 10 min. The reaction mixturewas diluted with water and extracted with EtOAc (4×30 mL). The combinedorganic layer was washed with water (4×30 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to afford crudeproduct, which was purified by column chromatography using neutralalumina and 0.5% MeOH-DCM to yield2,8-dimethyl-5-quinolin-3-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CDCl₃, freebase) δ (ppm): 9.0 (s, 1H), 8.25 (s, 1H), 8.1 (d,1H), 7.8 (d, 1H), 7.7 (t, 1H), 7.6 (t, 1H), 7.5 (d, 1H), 7.2 (s, 1H),7.1 (d, 1H), 3.62 (s, 2H), 3.0 (t, 2H), 2.7 (t, 2H), 2.6 (s, 3H), 2.42(s, 3H).

Example 232 Preparation of Compound No. 322

To a solution of7,8-dichloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (100 mg,0.392 mmol) in DMF (2 mL) were added sodium hydride (60 mg, 1.17 mmol)and 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (300 mg, 0.98mmol). The reaction mixture was irradiated in a microwave reactor at 90°C. for 1 h. The reaction mixture was cooled to RT and quenched withwater. The aqueous layer was extracted with EtOAc (3×10 mL). The organiclayer was washed with water (2×10 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford crude product,which was purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 8.37 (s, 1H), 8.18 (d, 1H), 7.7 (d, 1H), 7.61 (s, 1H), 7.39 (s,1H), 4.68 (m, 1H), 4.48 (t, 2H), 4.37 (m, 1H), 3.92 (m, 1H), 3.57 (m,1H), 3.2 (m, 4H), 3.1 (s, 3H), 2.7 (s, 3H).

Example 233 Preparation of Compound No. 323

To a degassed solution of2,8-dimethyl-5-quinolin-3-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(60 mg, 0.170 mmol) in MeOH (5 mL), were added Pd—C (30 mg, 50% w/w) andammonium formate (54 mg, 0.857 mmol) under nitrogen. The reactionmixture was stirred at 75° C. for 1 h, filtered through a Celite bed andwashed with MeOH (10 mL). The filtrate was concentrated under reducedpressure to afford crude product, which was purified by reverse phaseHPLC to yield the desired compound. ¹H NMR (CD₃OD, TFA salt) δ (ppm):8.3 (d, 2H), 8.0 (d, 1H), 7.9 (m, 2H), 7.70 (t, 1H), 7.3 (s, 1H), 7.21(d, 1H), 6.98 (d, 1H), 6.82 (s, 2H), 4.78 (d, 1H), 4.4 (d, 1H), 3.8 (m,1H), 3.58 (m, 1H), 3.1 (m, 5H), 2.38 (s, 3H).

Example 234 Preparation of Compound No. 324

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(200 mg, 1.0 mmol) in DCM (4 mL) were added powdered KOH (392 mg, 7.0mmol) and phenylamine (111 mg, 1.2 mmol). The reaction mixture wasstirred at 85° C. for 2 h. The reaction mixture was diluted with water(20 mL) and extracted with DCM (3×20 mL). The combined organic layer waswashed with water (3×30 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude material, which waspurified by silica gel column chromatography (3% MeOH-DCM), followed byreverse phase HPLC to yield(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-ylmethyl)-phenyl-amine(20 mg). ¹H NMR (CD₃OD, freebase) δ (ppm): 7.4 (d, 1H), 7.07 (s, 1H),7.0 (t, 2H), 6.97 (d, 1H), 6.67 (d, 2H), 6.6 (t, 1H), 5.42 (s, 2H), 3.7(s, 2H), 3.07 (t, 2H), 2.9 (t, 2H), 2.58 (s, 3H), 2.4 (s, 3H).

Example 235 Preparation of Compound No. 325

To a solution of6,9-dichloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg,0.392 mmol), in DMF (2 mL) were added sodium hydride (60 mg, 1.3 mmol)and 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (285 mg,0.980 mmol). The reaction mixture was irradiated in a microwave reactorat 90° C. for 1 h. The reaction mixture was cooled to RT, quenched withwater and extracted with EtOAc (3×10 mL). The organic layer was washedwith water (2×10 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude product, which waspurified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.41(s, 1H), 8.18 (d, 1H), 7.78 (d, 1H), 7.1 (d, 1H), 7.06 (d, 1H), 5.1 (m,1H), 4.8 (t, 2H), 4.6 (m, 1H), 3.8 (m, 1H), 3.57 (m, 1H), 3.22 (m, 4H),3.18 (s, 3H), 2.7 (s, 3H).

Example 236 Preparation of Compound No. 326

To a stirred solution of3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanethioamide(0.287 g, 1.0 mmol) in EtOH.HCl (3 mL) was added2-bromo-4′-chloroacetophenone (0.349 g, 1.5 mmol). The reaction mixturewas stirred at 82° C. for 16 h. Solvent was removed under reducedpressure. The residue was basified with 1N NaOH solution and extractedwith EtOAc (50 mL). The organic layer was dried over anhydrous sodiumsulfate and concentrated to afford crude product, which was purified bycolumn chromatography to yield the desired product. ¹H NMR (CDCl₃,freebase) δ (ppm): 7.8 (d, 2H), 7.4 (d, 2H), 7.3 (s, 1H), 7.2 (m, 2H),6.98 (d, 1H), 4.46 (t, 2H), 3.6 (s, 2H), 3.4 (t, 2H), 2.1-2.78 (m, 4H),2.53 (s, 3H), 2.4 (s, 3H).

Example 237 Preparation of Compound No. 327

To a de-aerated solution of6-bromo-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(85 mg, 0.215 mmol) and potassium carbonate (89 mg, 0.642 mmol) in1,2-dimethoxyethane-water (2:1) were added 3-methylthiophene-2-boronicacid pinacol ester (96 mg, 0.428 mmol) and Pd(PPh₃)₄ (17 mg, 0.015mmol). The reaction mixture was stirred at 90° C. for 45 min andconcentrated to dryness. The residue was dissolved in EtOAc (50 mL) andwashed with water (20 mL). The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to afford crudeproduct, which was purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFAsalt) δ (ppm): 8.0 (s, 1H), 7.77 (s, 2H), 7.47 (s, 1H), 7.38 (s, 1H),7.02 (s, 1H), 6.9 (s, 1H), 4.78 (m, 1H), 4.38 (m, 1H), 4.1 (bs, 1H), 4.0(m, 1H), 3.9 (bs, 1H), 3.6 (m, 1H), 3.1-3.27 (m, 5H), 2.8 (t, 2H), 2.7(s, 3H), 2.4 (s, 3H), 1.99 (s, 3H).

Example 238 Preparation of Compound No. 328

A mixture of 2-bromo-5-methyl-pyridine (250 mg, 1.45 mmol),5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (391mg, 1.74 mmol), TBAF.3H₂O (1.374 g, 4.36 mmol) and dichlorobistriphenylphosphine palladium(II) (51 mg, 0.072 mmol) was stirred at85° C. for 10 min. The reaction mixture was poured into water andextracted with EtOAc (3×100 mL). The organic layer was washed with water(3×100 mL), dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by column chromatography (neutral alumina,eluent-0.5% MeOH in DCM) to yield2,8-dimethyl-5-(5-methyl-pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CDCl₃, freebase) δ (ppm): 8.41 (s, 1H), 7.5 (m, 2H), 7.4 (d,1H), 7.18 (s, 1H), 7.08 (d, 1H), 3.6 (s, 2H), 3.0 (t, 2H), 2.83 (t, 2H),2.58 (s, 3H), 2.42 (s, 3H), 2.37 (s, 3H).

Example 239 Preparation of Compound No. 329

To a degassed solution of2,8-dimethyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-1-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(276 mg, 0.753 mmol), 5-bromo-2-propylpyridine (100 mg, 0.502) andpotassium carbonate (208 mg, 1.507 mmol) in DME (2 mL) and water (1 mL)was added Pd(PPh₃)₄ (40.6 mg, 0.035 mmol), followed by nitrogen purging.The reaction mixture was refluxed for 45 min. At that point, TLC showedno starting material. The reaction mixture was cooled to RT and dilutedwith EtOAc. The aqueous layer was extracted with EtOAc (3×6 mL) and thecombined organic layer dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure to afford crude product, which waspurified by reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.8(s, 1H), 8.36 (d, 1H), 7.62 (d, 1H), 7.3 (s, 1H), 7.2 (s, 1H), 7.16 (d,1H), 7.05 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.83 (bs, 1H), 3.4 (bs,1H), 3.18 (m, 2H), 3.1 (s, 3H), 2.9 (t, 2H), 2.4 (s, 3H), 2.0 (s, 3H),1.8 (m, 2H), 1.0 (t, 3H).

Example 240 Preparation of Compound No. 330

A mixture of 4-bromobenzenesulfonamide (200 mg, 0.84 mmol),5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (391mg, 1.0 mmol), TBAF.3H₂O (793 mg, 2.5 mmol) and dichloro bis(triphenylphosphine) palladium (II) (29 mg, 0.042 mmol) was stirred at 85° C. formin. The reaction mixture was poured into water and extracted with EtOAc(3×50 mL). The organic layer was washed with water (3×100 mL), driedover anhydrous sodium sulfate and concentrated to afford crude material,which was purified by column chromatography using neutral alumina and 5%MeOH-DCM, followed by reverse phase HPLC to yield4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-ylethynyl)-benzenesulfonamide.¹H NMR (CD₃OD, HCl salt) δ (ppm): 7.92 (d, 2H), 7.7 (d, 2H), 7.58 (d,1H), 7.38 (s, 1H), 7.23 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.96 (m, 1H),3.63 (m, 1H), 3.37 (m, 2H), 3.18 (s, 3H), 2.42 (s, 3H).

Example 241 Preparation of Compound No. 331

To a degassed solution of(Z)-2,8-dimethyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-1-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(140 mg, 0.382 mmol), 5-bromo-2-(trifluoromethyl)pyridine (87 mg, 0.382)and potassium carbonate (158 mg, 1.147 mmol) in DME (2 mL) and water (1mL) was added Pd(PPh₃)₄ (20 mg, 0.017 mmol), followed by nitrogenpurging. The reaction mixture was refluxed for 45 min. At that point,TLC showed no starting material. The reaction mixture was diluted withwater and extracted with EtOAc. The combined organic layer dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford crude material, which was purified by reverse phase HPLC. ¹H NMR(CD₃OD, TFA salt) δ (ppm): 9.0 (s, 1H), 8.27 (d, 1H), 7.88 (d, 1H), 7.37(s, 1H), 7.25 (s, 1H), 7.18 (d, 1H), 7.1 (d, 1H), 4.7 (d, 1H), 4.4 (d,1H), 3.82 (bs, 1H), 3.6 (m, 1H), 3.37 (m, 1H), 3.2 (m, 1H), 3.6 (s, 3H),2.42 (s, 3H), 2.01 (s, 3H).

Example 242 Preparation of Compound No. 332

To a de-aerated solution of2,8-dimethyl-5-naphthalen-2-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(50 mg, 0.14 mmol) in MeOH (5 mL), palladium hydroxide (25 mg, 50% w/w)and ammonium formate (45 mg, 0.71 mmol) were added. The reaction mixturewas stirred at 80° C. for 1 h. The progress of reaction was monitored byTLC and LCMS. The reaction mass was filtered through Celite and washedthe residue with MeOH (10 mL). The filtrate was concentrated underreduced pressure to afford crude material, which was purified by reversephase HPLC to yield2,8-dimethyl-5-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.26 (d, 1H), 7.22 (d, 1H), 7.02 (d,1H), 6.9 (d, 1H), 6.63 (d, 1H), 6.58 (s, 1H), 4.6 (d, 1H), 4.4 (m, 1H),4.2 (t, 2H), 3.62 (m, 1H), 3.02 (m, 1H), 2.9 (m, 4H), 3.0 (s, 3H), 2.7(bs, 2H), 2.6 (bs, 2H), 2.4 (s, 3H), 1.8 (bs, 4H).

Example 243 Preparation of Compound No. 333

A mixture of 4-bromo-benzenesulfonamide (200 mg, 0.84 mmol),9-ethynyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (228 mg, 1.01mmol), TBAF.3H₂O (801 mg, 2.54 mmol) and dichlorobis(triphenylphosphine) palladium(II) (30 mg, 0.042 mmol) was stirred at85° C. for 10 min. The reaction mixture was poured into water andextracted with EtOAc (3×25 mL). The organic layer was washed with water(3×30 mL), dried over anhydrous sodium sulfate and evaporated to affordcrude material, which was purified by reverse phase HPLC to yield4-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-ylethynyl)-benzenesulfonamide.¹H NMR (CDCl₃, freebase) δ (ppm): 7.9 (d, 2H), 7.6 (d, 2H), 7.4 (d, 1H),7.3 (s, 1H), 7.1 (d, 1H), 3.78 (s, 2H), 2.82 (t, 2H), 2.79 (t, 2H), 2.6(s, 3H), 2.42 (s, 3H).

Example 244 Preparation of Compound No. 334

A mixture of 5-bromo-thiophene-2-sulfonic acid amide (200 mg, 0.8 mmol),5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (222mg, 0.9 mmol), TBAF.3H₂O (756 mg, 2.4 mmol) and dichloro bis(triphenylphosphine) palladium (II) (28 mg, 0.04 mmol) was stirred at 85° C. for10 min. The reaction mixture was poured into water and extracted withEtOAc (3×50 mL). The organic layer was washed with water (3×100 mL),dried over anhydrous sodium sulfate and concentrated to afford crudematerial, which was purified by column chromatography using neutralalumina and 5% MeOH-DCM, followed by reverse phase HPLC to yield5-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-ylethynyl)-thiophene-2-sulfonicacid amide. ¹H NMR (CD₃OD, HCl salt) δ (ppm): 7.57 (d, 1H), 7.46 (d,1H), 7.36 (m, 2H), 7.21 (d, 1H), 4.42 (s, 2H), 3.71 (s, 2H), 3.3 (m,2H), 3.1 (s, 3H), 2.42 (s, 3H).

Example 245 Preparation of Compound No. 335

To a degassed solution of3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene (201 mg, 1.0mmol), 1-(2-bromo-1-methyl-vinyl)-4-fluoro-benzene (279 mg, 1.3 mmol),potassium phosphate (530 mg, 2.5 mmol) in DMF (4 mL), L-proline (28 mg,0.25 mmol) and cuprous iodide (47 mg, 0.25 mmol) were added. Thereaction mixture was stirred at 120° C. for 8 h. The reaction mixturewas cooled to RT, diluted with water (20 mL) and extracted with EtOAc(4×20 mL). The organic layer was washed with water (5×20 mL), dried overanhydrous sodium sulfate and evaporated to afford crude material, whichwas purified by silica gel flash chromatography to yield9-[2-(4-fluoro-phenyl)-propenyl]-3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene.¹H NMR (CDCl₃, freebase) δ (ppm): 8.1 (s, 1H), 7.57 (m, 3H), 7.07 (t,2H), 6.92 (s, 1H), 3.62 (s, 2H), 2.8 (s, 4H), 2.6 (s, 3H), 2.4 (s, 3H),2.0 (s, 3H).

Example 246 Preparation of Compound Nos. 336 and 336a-b

To a solution of8-aza-10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (227mg, 1.0 mmol) in DMF (5 mL) was added sodium hydride (120 mg, 3.0 mmol).After stirring at RT for 15 min, 4-fluorophenethyl4-methyl-benzenesulfonate (1.47 g, 3 mmol) was added into the reactionmixture, which was stirred at RT for 12 h. The progress of reaction wasmonitored by TLC and LCMS. The reaction mixture was quenched withice-water and extracted with EtOAc (3×50 mL). The organic layer waswashed with water (3×100 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by reversephase HPLC to yield the title compound (125 mg). ¹H NMR (CDCl₃,freebase) δ (ppm): 8.18 (s, 1H), 7.53 (s, 1H), 6.82 (m, 4H), 4.86 (m,1H), 4.44 (m 1H), 4.26 (m, 1H), 3.47 (m, 1H), 3.3 (m, 2H), 3.12 (m, 2H),2.89 (q, 1H), 2.56 (m, 1H), 2.49 (m, 1H), 244 (s, 3H), 2.29 (m, 1H), 1.8(m, 1H). Separation by chiral HPLC provides enantiomers 336a-b.

Example 247 Preparation of Compound Nos. 337 and 337a-b

This compound can be prepared in analogous fashion to Compound Nos. 30and 30a-b, using 2-(2-methyloxiran-2-yl)oxazole as the oxirane reagent.Separation by chiral HPLC provides enantiomers 337a-b.

Example 248 Preparation of Compound Nos. 338 and 338a-b

To an ice-cooled stirred solution of2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol(2.5 g, 7.78 mmol) in DMF (5 mL) was added sodium hydride (373 mg, 15.56mmol). After stirring for 20 min, heptanoyl chloride (1.9 g, 13.23 mmol)was added into the reaction mixture, which was stirred at 0° C. for 30min. The progress of reaction was monitored by LCMS and TLC. Thereaction mixture was quenched with ice water (200 mL) and extracted withEtOAc (400 mL). The combined organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby silica gel column chromatography (6% MeOH-DCM), followed by reversephase HPLC to yield heptanoic acid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (20 mg). ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.74 (s, 2H), 7.91 (s,2H), 7.28 (m, 2H), 7.04 (t, 1H), 6.2 (m 1H), 4.7 (d 1H), 4.59 (m, 2H),4.3 (m, 1H), 3.5 (t, 1H), 3.34 (m, 1H), 3.31 (m, 2H), 3.12 (s, 3H), 2.4(s, 3H), 2.3 (m, 2H), 2.1 (m, 1H), 1.35 (m, 2H), 1.22 (m, 2H), 1.15 (m,3H), 0.86 (t, 3H). Separation by chiral HPLC provides enantiomers338a-b.

Example 249 Preparation of Compound Nos. 339 and 339a-b

To a solution of9-chloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (1.0 g, 4.27mmol) in DMF (10 mL) was added potassium tert-butoxide (717.9 mg, 6.41mmol). After stirring at RT for 15 min, 2-(3,4-difluorophenyl)oxirane(1.33 g, 8.54 mmol) was added into the reaction mixture, which wasstirred at RT for 3 h. The progress of reaction was monitored by TLC andLCMS. The reaction mixture was quenched with ice-cold water andextracted with EtOAc. The organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by reverse phase HPLC to yield the titlecompound, which was resolved by chiral preparative HPLC. ¹H NMR (DMSO,TFA salt) δ (ppm): 7.62-7.50 (t, 1H), 7.50-7.30 (t, 3H), 7.25-7.00 (m,2H), 4.85-4.75 (m, 1H), 4.30-4.20 (t, 2H), 3.80-3.60 (m, 4H), 3.25-3.10(m, 4H), 2.90 (s, 3H).

Example 250 Preparation of Compound Nos. 340 and 340a-d

This compound can be prepared in analogous fashion to Compound Nos. 30and 30a-b, using 5-(oxiran-2-yl)-1H-1,2,3-triazole as the oxiranereagent. Separation by chiral HPLC provides diastereomers 340a-d.

Example 251 Preparation of Compound Nos. 341 and 341a-d

This compound can be prepared in analogous fashion to Compound Nos. 30and 30a-b, using 5-(oxiran-2-yl)-1H-tetrazole as the oxirane reagent.Separation by chiral HPLC provides diastereomers 341a-d.

Example 252 Preparation of Compound Nos. 342 and 342a-d

This compound can be prepared in analogous fashion to Compound Nos. 30and 30a-b, using 2-(oxiran-2-yl)-1H-imidazole as the oxirane reagent.Separation by chiral HPLC provides diastereomers 342a-d.

Example 253 Preparation of Compound Nos. II-270 and II-270a-b

These compounds can be synthesized in an analogous fashion to CompoundNos. 55 and 55a-b, using3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,2,6,9-tetraaza-fluorene as thecarboline portion and 4-(2-methyloxiran-2-yl)pyridine as the epoxide.Separation by chiral HPLC provides enantiomers II-270a-b.

Example 254 Preparation of Compound Nos. II-1 and II-1a-b

To a solution of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanamine(500 mg, 1.56 mmol) in DCM (5 mL) was added pyridine (185 mg, 2.3 mmol).After stirring for 5 min at RT, a solution of acetyl chloride (147.2 mg,1.88 mmol) in DCM (0.5 mL) was added into the reaction mixture, whichwas stirred at RT for 16 h. The reaction mixture was diluted with DCMand washed with saturated aq NaHCO₃ solution. The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was triturated with ether to yieldN-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethyl)acetamide(500 mg). ¹H NMR (CDCl₃, Free base) δ (ppm): 8.42 (d, 2H), 7.25 (s, 1H),7.15 (d, 1H), 6.92 (d, 2H), 6.9 (d, 1H), 6.2 (d, 1H), 5.3 (q, 1H), 4.4(dd, 1H), 4.25 (dd, 1H), 3.58 (dd, 2H), 2.6 (m, 2H), 2.55 (s, 3H), 2.43(s, 3H), 2.3 (m, 2H), 2.03 (s, 3H). Separation by chiral HPLC providedenantiomers II-1a-b.

Example 255 Preparation of Compound No. II-2

Crude2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethylmethanesulfonate was taken in NMP (5 mL), and KOH powder (873 mg, 15.5mmol) was added at RT and the mixture stirred at 80° C. for 14 h. Theproduct was detected by LCMS. Water was added to the reaction mixture,which was extracted with EtOAc. The organic layer was dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was chromatographed on silica gel using 5% MeOH-DCM toafford 400 mg of the title compound. ¹H NMR (DMSO, Formate salt) δ(ppm): 8.55-8.50 (d, 2H), 8.05-8.00 (d, 1H), 7.85-7.80 (d, 1H),7.65-7.55 (d, 2H), 7.25 (s, 1H), 7.15-7.10 (m, 1H), 6.80-6.75 (d, 1H),3.58 (s, 2H), 3.05 (t, 2H), 2.78 (t, 2H), 2.41 (s, 3H), 2.38 (s, 3H).

Example 256 Preparation of Compound No. II-3

To a stirred cooled (−70° C.) solution of2-methyl-5-[2-(6-methyl-pyridin-3-yl)-propenyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid methyl ester (100 mg, 0.26 mmol) in THF (10 mL) was addedportionwise LAH (30 mg, 0.79 mmol) and stirring continued at RT for 4 h.The reaction mixture was cooled to −70° C. and quenched with water (0.1mL), 15% NaOH (0.1 mL) and water (0.2 mL). The solid was filtered andthe filtrate concentrated to afford crude material, which was purifiedby reverse phase HPLC. ¹H NMR (CD₃OD, Formate salt) δ (ppm): 8.67 (s,1H), 8.0 (d, 1H), 7.5 (s, 1H), 7.4 (d, 1H), 7.27 (d, 1H), 7.23 (d, 1H),7.1 (s, 1H), 4.7 (s, 2H), 4.42 (s, 2H), 3.6 (t, 2H), 3.1 (t, 2H), 3.05(s, 3H), 2.6 (s, 3H), 1.28 (s, 3H).

Example 257 Preparation of Compound Nos. II-4 and II-4-a-d

6-(2-Azido-2-pyridin-4-yl-ethyl)-9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene(400 mg, 1.07 mmol) was dissolved in ethanol-water (10 mL:1 mL). Zincdust (280 mg, 4.3 mmol) and ammonium chloride (228 mg, 4.3 mmol) wereadded and the reaction mixture was heated at 80° C. for 1 h. Afterconsumption of starting material, the reaction mixture was filteredthrough Celite and filtrate was concentrated to obtain the residue. Theresidue was basified with aq ammonia and extracted with EtOAc (2×100mL). The combined organic layer was dried over anhydrous sodium sulfateand concentrated to obtain the crude product, which was purified byreverse phase chromatography to obtain 40 mg of2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyridin-4-yl-ethylamineas the TFA salt. ¹H NMR (CDCl₃, freebase): δ (ppm): 8.58 (d, 2H), 7.28(d, 1H), 7.25 (s, 1H), 7.23 (d, 2H), 7.1 (d, 1H), 4.9 (m, 1H), 4.42 (t,1H), 4.13 (dd, 1H), 3.63 (m, 1H), 3.4 (m, 2H), 3.01 (m, 2H), 2.71 (m,2H), 2.45 (s, 3H), 2.23 (m, 2H), 2.01 (m, 1H). Chiral HPLC separated theracemate into diastereomers II-4-a-d.

Example 258 Preparation of Compound Nos. II-5 and II-5a-d

To a solution of9-aza-10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (30mg, 0.13 mmol) in DMF (5 mL) was added NaH (16 mg, 0.4 mmol, 60%dispersion in mineral oil) at 0° C. and the mixture was stirred for 10min. 3-(2-Methyl-oxiranyl)-pyridine 36 mg, 0.26 mmol) was added and thereaction mixture was stirred overnight at RT. The reaction was monitoredby LCMS. The reaction mixture was quenched with MeOH (1 mL),concentrated under reduced pressure to obtain the crude product, whichwas purified by reverse phase column chromatography to obtain the pureproduct (3.3 mg) as the free base. ¹H NMR (CDCl₃, freebase): δ (ppm):9.1 & 8.91 (s, 1H), 8.8 & 8.7 (s, 1H), 8.6 & 8.5 (d, 1H), 7.6 & 7.8 (d,1H), 7.18 (s, 2H), 4.4 (dd, 1H), 4.2 (m, 2H), 3.32 (m, 2H), 2.7 (dd,1H), 2.66 (s, 3H), 1.99 (m, 2H), 1.9 (m, 2H), 1.76 & 1.67 (s, 3H), 1.6(m, 3H). Chiral HPLC separates the racemate into diastereomers II-5a-d.

Example 259 Preparation of Compound Nos. II-6 and II-6a-d

6-(2-Chloro-2-pyrazin-2-yl-propyl)-9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene(500 mg, 1.31 mmol) in 40% dimethylamine in water (30 mL) was heated at100° C. for 3 h. The reaction mixture was cooled at RT and extractedwith EtOAc (3×50 mL). The combined organic layer was dried overanhydrous sodium sulfate and concentrated to obtain the crude product,which was purified by reverse phase chromatography to obtain 62 mg ofdimethyl-[1-methyl-2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyrazin-2-yl-ethyl]-amine.¹H NMR (CD₃OD, TFA salt): δ (ppm): 8.06 (s, 1H), 7.48 (s, 1H), 7.21 (s,1H), 7.17 (d, 1H), 7.00 (d, 1H), 4.98 (t, 1H), 4.28 (d, 2H), 3.6 (m,3H), 3.39 (m, 2H), 3.2 (m, 1H), 3.15 (s, 6H), 2.8 (m, 1H), 2.7 (m, 1H),2.39 (s, 3H), 2.17 (m, 3H). Chiral HPLC separated the racemate intodiastereomers II-6a-d.

Example 260 Preparation of Compound Nos. II-7 and II-7a-d

Methanesulfonic acid2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyrazin-2-yl-ethylester (300 mg, 0.70 mmol) in 40% dimethylamine in water (20 mL) washeated at 90° C. for 1 h. The reaction mixture was cooled to RT andextracted with DCM (12×50 mL) The combined organic layer was dried overanhydrous sodium sulfate and concentrated to obtain the crude product,which was purified by reverse phase chromatography to obtain 60 mg ofdimethyl-[2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyrazin-2-yl-ethyl]-amine.¹H NMR (CD₃OD, TFA salt): δ (ppm): 8.1 (s, 1H), 7.4 (s, 1H), 7.1 (d,1H), 5.1 (t, 1H), 4.42 (m, 2H), 3.6 (m, 3H), 3.2 (m, 1H), 3.17 (m, 1H),3.15 (s, 6H), 2.85 (m, 2H), 2.63 (m, 1H), 2.42 (s, 3H), 2.3 (m, 2H),2.15 (m, 1H). Chiral HPLC separates the racemate into diastereomersII-7a-d.

Example 261 Preparation of Compound Nos. II-8 and II-8a-b

Methanesulfonicacid-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester(300 mg, 0.75 mmol) in 70% ethylamine in water (15 mL) was heated at100° C. for 18 h. The reaction mixture was cooled to RT and extractedwith EtOAc (2×100 mL). The combined organic layer was washed with water(2×20 mL), dried over anhydrous sodium sulfate and concentrated toobtain the crude product, which was purified by reverse phasechromatography to obtain 55 mg of[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-ethyl-amine.¹H NMR (DMSO, TFA salt): δ (ppm): 8.5 (d, 2H), 7.3 (d, 1H), 7.2 (m, 3H),6.9 (d, 1H), 4.7 (m, 2H), 4.43 (m, 2H), 4.1 (d, 1H), 3.3 (m, 1H), 3.0(m, 2H), 2.85 (d, 6H), 2.8 (m, 1H), 2.5 (m, 2H), 2.3 (s, 3H), 1.22 (s,3H). Chiral HPLC separates the racemate into enantiomers II-8a-b.

Example 262 Preparation of Compound Nos. II-9 and II-9a-b

Methanesulfonic acid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester(240 mg, 0.60 mmol) was dissolved in 10 mL of 70% cyclopentylaminesolution in water and heated at 100° C. for 18 h. The reaction mixturewas cooled to RT and concentrated to obtain the crude product, which waspurified by reverse phase chromatography to obtain 11 mg ofcyclopentyl-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-amine.¹H NMR (CDCl₃, freebase): δ (ppm): 8.51 (d, 2H), 7.17 (m, 4H), 7.003 (d,1H), 4.16 (m, 2H), 4.05 (dd, 1H), 3.79 (dd, 2H), 2.9 (m, 1H), 2.83 (m,2H), 2.55 (s, 3H), 2.44 (s, 3H), 2.39 (m, 1H), 1.99 (s, 2H), 1.7 (m,2H), 1.5 (m, 2H), 1.4 (m, 1H), 1.9 (m, 2H). Chiral HPLC separates theracemate into enantiomers II-9a-b.

Example 263 Preparation of Compound Nos. II-10 and II-10a-b

2-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylamine(200 mg, 0.62 mmol) was dissolved in 15 mL DCM, acetone (108 mg, 1.87mmol), acetic acid (0.5 mL) was added and the reaction mixture wasstirred at RT overnight. Sodiumcyanoborohydride (117 mg, 1.87 mmol) wasadded and stirred at for 1 h. The reaction mixture was diluted with DCM(300 mL) and washed with saturated bicarbonate solution (200 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedto obtain the crude product, which was purified by reverse phasechromatography to obtain 120 mg of[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-isopropyl-amineas the TFA salt. ¹H NMR (CD₃OD, TFA salt): δ (ppm): 8.52 (m, 2H), 7.42 b(s, 2H), 7.30 b (s, 1H), 7.22 (s, 1H), 7.02 (m, 1H), 4.8 (m, 1H), 4.58(m, 2H), 4.23 (t, 1H), 3.72 (m, 1H), 3.4 (m, 3H), 3.13 (m, 2H), 2.99 (d,3H), 2.39 (s, 3H), 1.43 (d, 3H), 1.34 (d, 3H). Chiral HPLC separates theracemate into enantiomers II-10a-b.

Example 264 Preparation of Compound Nos. II-11 and II-11a-b

To a solution of5-(2-azido-2-(4-fluorophenyl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(1 g, 2.75 mmol) in ethanol-water (40-5 mL) was added ammonium chloride(590 mg, 11.02 mmol) and zinc dust (716 mg, 11.02 mmol) and heated at100° C. for 1 h. After complete conversion of starting material (TLC),ethanol was removed under reduced pressure and 50 mL additional waterwas added and extracted with DCM (3×100 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated under vacuum to obtainthe crude product, which was purified by reverse phase HPLC to obtain2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanamine(730 mg) as the TFA salt. ¹H NMR (CD₃OD, TFA salt): δ (ppm): 7.27 (m,1H), 7.21 (m, 3H), 7.10 (m, 3H), 4.60 (m, 3H), 4.50 (m, 1H), 4.24 (m,1H), 3.69 (m, 1H), 3.44 (m, 1H), 3.04 (m, 1H), 2.96 (s, 3H), 2.56 (m,1H), 2.41 (s, 3H). Chiral HPLC separated the racemate into enantiomersII-11a-b.

Example 265 Preparation of Compound Nos. II-12 and II-12a-b

2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethylmethane sulfonate (250 mg, 0.6 mmol) in methyl amine (40% solution inwater, 5 mL) was heated at 100° C. for 4 h. The progress of the reactionwas monitored by TLC and LCMS. 10 mL of water was added to the reactionmixture and then extracted with EtOAc (2×50 mL). The organic layer wasdried over anhydrous sodium sulfate and concentrated under vacuum toobtain the crude product, which was purified by reverse phase HPLC toobtain2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)-N-methylethanamine (30 mg) as the TFA salt. ¹H NMR (CDCl₃, freebase): δ (ppm):7.32 (t, 2H), 7.24 (m, 1H), 7.21 (s, 1H), 7.01 (m, 3H), 3.91 (m, 2H),3.65 (dd, 2H), 2.80 (m, 3H), 2.62 (m, 1H), 2.54 (s, 3H), 2.45 (s, 3H),2.14 (s, 3H). Chiral HPLC separated the racemate into enantiomersII-12a-b.

Example 266 Preparation of Compound Nos. II-13 and II-13a-b

Methanesulfonicacid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester(300 mg, 0.75 mmol) was dissolved in 70% cyclobutylamine in water (6 mL)and heated at 100° C. for 18 h. The reaction mixture was concentrated toobtain the crude product, which was purified by reverse phasechromatography to obtained 90 mg ofcyclobutyl-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-amineas the TFA salt. ¹H NMR (CD₃OD, TFA salt): δ (ppm): 8.6 (dd, 2H), 7.63(d, 1H), 7.54 (d, 1H), 7.19 (s, 1H), 7.10 (d, 1H), 6.99 (d, 1H), 4.82(m, 2H), 4.72 (m, 1H), 4.6 (m, 1H), 4.23 (t, 1H), 3.8 (m, 2H), 3.5 (m,1H), 3.2 (m, 1H), 3.07 (d, 3H), 2.7 (m, 1H), 2.37 (s, 3H), 2.5 (m, 3H),2.1 (m, 1H), 1.8 (m, 2H). Chiral HPLC separated the racemate intoenantiomers II-13a-b.

Example 267 Preparation of Compound Nos. II-14 and II-14a-b

2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanamine(250 mg, 0.741 mmol), formaldehyde 37-40% solution (5 mL) and formicacid (0.25 mL) was heated at 100° C. for 2 h. After the completion ofreaction (TLC and LCMS), the reaction mixture was cooled to RT,neutralized by saturated sodium bicarbonate and extracted into DCM (2×50mL). The combined organic layer was washed with water (50 mL), driedover anhydrous sodium sulfate and concentrated under reduced pressure toobtain 250 mg of2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)-N,N-dimethylethanamine.¹H NMR (CDCl₃, freebase): δ (ppm): 7.13 (s, 1H), 7.05 (d, 1H), 7.02 (t,2H), 6.88 (m, 3H), 4.56 (dd, 1H), 3.99 (m, 1H), 3.64 (d, 1H) 3.54 (dd,1H), 3.46 (d, 1H), 2.79 (m, 1H), 2.6 (m, 2H), 2.45 (s, 3H), 2.42 (s,3H), 2.3 (s, 6H), 1.9 (m, 1H). Chiral HPLC separated the racemate intoenantiomers II-14a-b.

Example 268 Preparation of Compound Nos. II-15 and II-15a-b

1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol(2.0 g, 5.97 mmol) was dissolved in DMF (20 ml), sodium hydride (716 mg,17.9 mmol) was added and the mixture stirred at RT for 20 min. Aceticanhydride (913 mg, 8.95 mmol) was added dropwise at the same temperatureand stirring continued for 1.5 h. The reaction was monitored by TLC andLCMS. The reaction mixture was poured into 250 mL ice water andextracted with EtOAc (3×200 mL), washed with water (3×300 mL), driedover anhydrous sodium sulfate and concentrated to obtain the crudeproduct that was purified by column chromatography (silica gel: 100-200mesh, eluent:—6-8% MeOH in DCM) to obtain 110 mg of acetic acid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-methyl-1-pyridin-3-yl-ethylester, which was followed by chiral separation. ¹H NMR (CD₃OD, Freebase) δ (ppm): 8.38 (d, 1H), 8.15 (s, 1H), 7.45 (d, 1H), 7.22 (t, 1H),7.1 (s, 1H), 7.0 (s, 1H), 6.8 (d, 1H), 4.43 (d, 1H), 4.2 (d, 1H), 3.7(d, 1H), 3.5 (d, 1H), 2.8 (m, 2H), 2.53 (m, 1H), 2.5 (s, 3H), 2.4 (s,3H), 2.2 (m, 1H), 2.07 (d, 6H). Separation by chiral HPLC providedenantiomers II-15a-b.

Example 269 Preparation of Compound Nos. II-16 and II-16a-b

1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol(5.0 g, 14.9 mmol) was dissolved in DMF (100 mL) and sodium hydride (1.8g, 45 mmol) was added, and the mixture stirred at RT for 15 min.Pivaloyl chloride (3 g, 25 mmol) was added dropwise at the sametemperature, and the mixture stirred for 45 min. The reaction wasmonitored by TLC and LCMS. The reaction mixture was poured into 400 mLice water to obtain a solid that was filtered. The solid was dissolvedin DCM, dried over sodium sulfate and concentrated to obtain the crudeproduct that was purified by column chromatography (silica gel: 100-200mesh, Eluent:—4-6% MeOH in DCM) to obtain 1.8 g of2,2-dimethyl-propionic acid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-methyl-1-pyridin-3-yl-ethylester. The product was further purified by chiral preparative HPLC togive enantiomers II-16a and II-16b. ¹H NMR (CDCl₃, Free base): δ (ppm):8.55 (d, 1H), 8.5 (s, 1H), 7.2 (d, 1H), 7.18 (m, 3H), 6.9 (d, 1H), 4.3(dd, 2H), 3.65 (d, 1H), 3.52 (d, 1H), 2.65 (m, 2H), 2.5 (m, 2H), 2.5 (s,3H), 2.4 (s, 3H), 2.3 (d, 1H), 2.0 (s, 3H), 2.0 (m, 1H), 1.2 (s, 9H).

Example 270 Preparation of Compound Nos. II-17 and II-17a-d

To a solution of11-aza-10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (120mg, 0.52 mmol) in DMF (5 mL) was added NaH (31 mg, 1.06 mmol, 60%dispersion in mineral oil) at 0° C. and the reaction mixture was stirredfor 10 min. 3-(2-Methyl-oxiranyl)-pyridine 143 mg, 1.06 mmol) was addedand the reaction mixture was stirred at RT overnight. The reaction wasmonitored with LCMS. The reaction mixture was quenched with MeOH (2 mL),concentrated under reduced pressure to obtain the crude product, whichwas purified by reverse phase column chromatography to obtain the 30 mgof product as the free base. ¹H NMR (CDCl₃, freebase): δ (ppm): 8.72 &8.69 (s, 1H), 8.25 (t, 1H), 7.62 & 7.6 (d, 1H), 7.43 (t, 1H), 7.22 &7.19 (m, 1H), 6.86 (t, 1H), 4.25 (m, 2H), 3.2 (m, 1H), 2.99 (m, 1H),2.85 (t, 2H), 2.7 (m, 1H), 2.626 (s, 3H), 2.5 (m, 2H), 2.4 (m, 1H), 2.15(m, 1H), 1.85 (m, 2H), 1.69 & 1.66 (s, 3H). Chiral HPLC separates theracemate into diastereomers II-17a-d.

Example 271 Preparation of Compound No. II-18

To a solution of2,6,9-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.466mmol) in DMF (2 mL) were added sodium hydride (60 mg, 1.3 mmol) and2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (337.5 mg, 1.16mmol). The reaction mixture was irradiated in a microwave reactor at 90°C. for 1 h. The reaction mixture was cooled to RT, quenched with waterand extracted with EtOAc (3×10 mL). The organic layer was washed withwater (2×10 mL), dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford the crude product, which was purifiedby reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.1 (m, 2H),7.7 (d, 1H), 6.6 (d, 2H), 4.98 (m, 1H), 4.5 (m, 1H), 4.4 (t, 2H), 3.82(bs, 1H), 3.5 (bs, 1H), 3.2 (t, 2H), 3.1 (m, 5H), 2.65 (s, 3H), 2.5 (s,3H), 2.31 (s, 3H).

Example 272 Preparation of Compound Nos. II-19 and II-19a-b

1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol(3.35 g, 10.0 mmol), isonicotinic acid (1.23 g, 10 mmol), DCC (5.0 g,24.0 mmol) and DMAP (1.2 g, 10 mmol) were suspended in DCM (300 mL) andthe resultant mixture was stirred overnight under nitrogen atmosphere.The reaction was monitored by LCMS. The reaction mixture was filtered toremove N,N-dicyclohexyl urea formed during the reaction. The filtratewas washed with water (3×300 mL), dried over anhydrous sodium sulfateand concentrated under reduced pressure to obtain the crude productwhich was purified by column chromatography (neutral alumina; eluent:0.5-1% MeOH in DCM) to obtain the product. The product obtained wastriturated with diethyl ether (30 mL) to obtain the pure product (400mg). ¹H NMR (CDCl₃, freebase): δ (ppm): 8.71 (d, 2H), 8.58 (s, 1H), 8.56(d, 1H), 7.64 (d, 2H), 7.32 (d, 1H), 7.21 (s, 1H), 7.18 (d, 2H), 6.97(d, 1H), 4.45 (dd, 2H), 3.65 (d, 1H), 3.57 (d, 1H), 2.7 (m, 1H), 2.52(m, 1H), 2.49 (s, 3H), 2.46 (s, 3H), 2.43 (m, 1H), 2.16 (s, 3H), 2.01(m, 1H). Separation by chiral HPLC provided enantiomers II-19a-b.

Example 273

Compound Nos. II-21, II-23, II-36, II-56, II-57, II-160, II-188-206,II-233, II-237 and II-254 were synthesized as described in PCTpublication WO2009/055828. Compound Nos. II-107 and II-164-165 weresynthesized as described in PCT publication WO2009/120720. Compound Nos.II-20, II-48-49, II-52-55, II-156-158 and II-161 were synthesized asdescribed in PCT publication WO2009/120717. Compound Nos. II-47, II-95,II-162-163 and II-166-187 were synthesized as described in PCTpublication WO2010/051501. Compound Nos. II-22, II-24-35, II-37-38,II-41-46, II-50-51, II-155 and II-159 were synthesized as described inPCT publication WO2010/051503. Compound No. II-219 was synthesized asdescribed in PCT publication WO2010/127177. Compound Nos. II-207-208,II-216-218 and II-228 were synthesized as described in PCT publicationWO2010/019417. Compound No. II-69 was synthesized as described in PCTpublication WO2011/038163. Compound Nos. II-79, II-86, II-234-236 andII-238-239 were synthesized as described in PCT publicationWO2011/038161. Compound Nos. II-72-74, II-87 and II-214 were synthesizedas described in PCT publication WO2011/038162. Compound Nos. II-66 andII-85 were synthesized as described in PCT publication WO2011/038164.

Example 274 Preparation of Compound No. II-39

To a solution of6-bromo-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg,0.359 mmol), in DMF (2 mL) were added sodium hydride (50 mg, 1.07 mmol)and 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (262 mg,0.899 mmol). The reaction mixture was irradiated in a microwave reactorat 90° C. for 1 h. The reaction mixture was cooled to RT, quenched withwater and extracted with EtOAc (3×10 mL). The organic layer was washedwith water (2×10 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude, which was purifiedby reverse phase HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.36 (s, 1H),8.17 (d, 1H), 7.7 (d, 1H), 7.21 (s, 1H), 7.18 (s, 1H), 4.8 (m, 1H), 4.62(t, 2H), 4.3 (m, 1H), 3.82 (m, 1H), 3.5 (m, 1H), 3.2 (m, 3H), 3.1 (m,4H), 2.7 (s, 3H), 2.38 (s, 3H).

Example 275 Preparation of Compound No. II-40

A solution of2,3,4,5-tetrahydro-2,4,4,8-tetramethyl-1H-pyrido[4,3-b]indole (228 mg, 1mmol) and KOH (448 mg, 8 mmol) in NMP was heated at 100° C. for 15 min.2-(Trifluoromethyl)-5-vinylpyridine (381 mg, 2.2 mmol) was addeddropwise into the reaction mixture and stirring continued at 45° C. for30 min. The reaction mixture was diluted with water and extracted withEtOAc (3×25 mL). The organic extract was washed with water (3×25 mL),dried over anhydrous sodium sulfate and evaporated in vacuo to affordcrude material, which was purified by silica gel column chromatographyusing 0-5% MeOH-DCM, followed by reverse phase HPLC to yield desiredcompound as the TFA salt (41 mg). ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.4(s, 1H), 7.8 (d, 1H), 7.72 (d, 1H), 7.24 (d, 2H), 7.02 (d, 1H), 4.67 (d,1H), 4.6 (t, 2H), 4.35 (d, 1H), 3.47 (d, 1H), 3.4 (d, 1H), 3.24 (t, 2H),3.17 (s, 3H), 2.4 (s, 3H), 1.48 (s, 3H), 1.45 (s, 3H).

Example 276 Preparation of Compound Nos. II-49 and II-49a-b

Sodium hydride (36 mg, 1.5 mmol) was dissolved in THF.2,6-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg, 0.05mmol) in THF was added dropwise at 0° C. to the NaH solution and thereaction mixture was stirred for 0.5 h. A solution of 2-(2-fluorophenyl)oxirane (103 mg, 0.075 mmol) in THF was added dropwise to the reactionmixture and was stirred at RT for 2 h. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction wasquenched with ice-water, the THF was evaporated and the aqueous layerwas extracted with EtOAc. The organic layer was dried over anhydroussodium sulfate. The crude compound was purified by column chromatographyto yield the desired compound (30 mg) which was stirred in ethanolic HClto yield2-(2,6-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-1-(2-fluorophenyl)ethanolhydrochloride salt. ¹H NMR (CDCl₃, Free base) δ (ppm): 7.6 (t, 1H), 7.3(m, 3H), 7.2 (t, 1H), 7.1 (t, 1H), 7.0 (d, 1H), 5.33 (d, 1H), 4.22 (d,1H), 3.95 (dd, 1H), 3.8 (d, 1H), 3.5 (d, 1H), 2.8 (m, 4H), 2.5 (s, 3H),2.4 (s, 3H). Separation by chiral HPLC provided enantiomers II-49a-b.

Example 277 Preparation of Compound Nos. II-57 and II-57a-b

2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.35 g, 6.65mmol) was taken in DMF (10 mL). NaH (0.9 g, 19.5 mmol) was added to itportionwise at RT and the mixture stirred for 15 min.2-Methyl-5-(oxiran-2-yl)pyridine (0.9 g, 6.65 mmol) was added to thereaction mixture dropwise at RT. After complete addition, the reactionmixture was stirred at RT for 2 h. The product was detected by LCMS. Thereaction mixture was quenched with MeOH and concentrated to dryness.Water (20 mL) was added and the reaction mixture was extracted in EtOAc(2×100 mL), the extracts dried over anhydrous sodium sulfate andconcentrated to obtain a dark brown oil. The crude product was purifiedby reverse phase chromatography to obtain pure material as a TFA salt(310 mg). ¹H NMR (CDCl₃, Free base) δ (ppm): 8.45 (s, 1H), 7.52 (d, 1H),7.2 (s, 1H), 7.19 (d, 1H), 7.12 (d, 1H), 6.97 (d, 1H), 5.0 (t, 1H), 4.18(dd, 2H), 3.61 (dd, 2H), 2.9 (m, 1H), 2.82 (m, 2H), 2.65 (m, 1H), 2.50(s, 3H), 2.48 (s, 3H), 2.41 (s, 3H). Separation by chiral HPLC providedenantiomers II-57a-b.

Example 278 Preparation of Compound Nos. II-58 and II-58a-b

1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-4-yl-propan-2-ol(350 mg. 1.0 mmol) was dissolved in 10 mL DCM and metachloro perbenzoicacid (216 mg, 1.2 mmol) was diluted in DCM and added dropwise at RT.After consumption of starting material by monitoring TLC & LCMS, thereaction mixture was concentrated and purified by reverse phasechromatography to obtain 200 mg of1-(2,8-dimethyl-2-oxy-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-4-yl-propan-2-ol.¹H NMR (CDCl₃, Free base) δ (ppm): 8.54 (d, 2H), 7.68 (d, 1H), 7.55 (d,1H), 7.28 (d, 2H), 7.22 (s, 1H), 7.10 (d, 1H), 6.63 (d, 1H), 4.06 (d,2H), 3.28 (t, 2H), 2.91 (t, 2H), 2.46 (s, 3H). Separation by chiral HPLCprovides enantiomers II-58a-b.

Example 279 Preparation of Compound No. II-59

To a de-aerated solution of2-allyl-8-methyl-5-[2-(6-methyl-pyridin-3-yl)-propenyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(750 mg, 2.1 mmol) in DCM (7.5 mL) were added 1,3-dimethylbarbutaricacid (984 mg, 6.302 mmol) and Pd(PPh₃)₄ (48 mg, 0.042 mmol), and thereaction mixture stirred for 1 h at RT. The reaction mixture wasconcentrated and the residue diluted with 25% saturated potassiumcarbonate and extracted with EtOAc (3×30 mL). The combined organic layerwas washed with water (2×25 mL), dried over anhydrous sodium sulfate andconcentrated to afford crude material, which was purified by columnchromatography using neutral alumina and 2% MeOH-DCM followed by reversephase HPLC to yield8-methyl-5-[2-(6-methyl-pyridin-3-yl)-propenyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(180 mg). ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.92 (s, 1H), 8.65 (d, 1H),7.90 (d, 1H), 7.36 (d, 2H), 7.18 (d, 1H), 7.16 (d, 1H), 4.50 (s, 2H),3.65 (t, 2H), 3.10 (t, 2H), 2.80 (s, 3H), 2.42 (s, 3H), 2.05 (s, 3H).

Example 280 Preparation of Compound No. II-60 and II-60a-b

To a solution of5-(2-hydroxy-2-pyridin-4-yl-ethyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid methyl ester (180 mg, 0.493 mmol) in dry THF (12 mL) wasportionwise added LAH (56 mg, 1.479 mmol) under nitrogen atmosphere, andthe reaction mixture stirred at RT for 2 h. The reaction mixture wascooled to −78° C. and quenched with ice water (0.6 mL), 10% NaOH (0.6mL) and water (1.8 mL), and the solid filtered. The filtrate wasconcentrated and the residue was purified by reverse phase HPLC to yield2-(8-hydroxymethyl-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol.¹H NMR (CD₃OD, freebase) δ (ppm): 8.4 (d, 2H), 7.4 (s, 1H), 7.27-7.38(m, 3H), 7.18 (d, 1H), 5.1 (t, 1H), 4.62 (s, 2H), 4.3 (d, 2H), 4.0 (dd,2H), 3.2 (m, 1H), 3.1 (m, 2H), 2.73 (m, 1H), 2.7 (s, 3H). Separation bychiral HPLC provides enantiomers II-60a-b.

Example 281 Preparation of Compound No. II-61

To a de-aerated solution of2,4,4,8-tetramethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (228 mg,1.00 mmol), potassium phosphate (466 mg, 2.20 mmol), L-proline (19 mg,0.10 mmol) and copper iodide (I) (23 mg, 0.20 mmol) in DMF (2 mL) wasadded 5-(1-bromoprop-1-en-2-yl)-2-methylpyridine (424 mg, 2.00 mmol),and the reaction mixture stirred at 120° C. for 20 h. The progress ofreaction was monitored by TLC and LCMS. The reaction mixture was dilutedwith water (20 mL) and extracted with EtOAc (3×10 mL). The combinedorganic layer was washed with water (3×20 mL), followed by brine (25mL), dried over anhydrous sodium sulfate and evaporated to afford crudematerial, which was purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFAsalt) δ (ppm): 8.97 (s, 1H), 8.66 (d, 1H), 7.9 (d, 1H), 7.42 (s, 1H),7.37 (s, 1H), 7.1 (q, 2H), 4.7 (m, 1H), 4.37 (m, 1H), 3.5 (m, 2H), 3.2(s, 3H), 2.8 (s, 3H), 2.42 (s, 3H), 1.97 (s, 3H), 1.5 (bs, 6H).

Example 282 Preparation of Compound Nos. II-62 and II-62a-b

To a degassed solution of1-(2-allyl-8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-4-yl-propan-2-ol(300 mg, 0.78 mmol) in DCM (20 mL) were added 1,3-dimethyl barbituricacid (368 mg, 2.3 mmol) and Pd(PPh₃)₄ (18 mg, 0.015 mmol). Afterstirring at RT for 30 min, the reaction mixture was diluted with DCM andwashed with saturated potassium carbonate solution. The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by reverse phase HPLC to yield1-(8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-4-yl-propan-2-ol.¹H NMR (CD₃OD, formate salt) δ (ppm): 8.4 (d, 2H), 7.48 (d, 2H), 7.4 (s,1H), 7.18 (d, 1H), 6.98 (d, 1H), 4.6 (bs, 1H), 4.4 (s, 2H), 4.3 (m, 2H),3.6 (m, 2H), 3.4 (m, 2H), 3.1 (m, 2H). Separation by chiral HPLCprovides enantiomers II-62a-b.

Example 283 Preparation of Compound Nos. II-63 and II-63a-b

To a solution of2-allyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (1000 mg,4.42 mmol) in DMF (10 mL) was portionwise added sodium hydride (526 mg,13.26 mmol). After stirring at RT for 5 min., 4-(oxiran-2-yl)pyridine(669 mg, 5.31 mmol) was added dropwise into the reaction mixture, whichwas stirred at RT for 16 h. Ice water was added into the reactionmixture and the solid mass obtained was filtered, washed with water(2×10 mL), hexane (2×50 mL) and ether to yield2-(2-allyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.6 (d, 2H), 7.24 (s, 1H), 7.2 (d,2H), 7.0 (d, 2H), 5.98 (m, 1H), 5.2 (dd, 2H), 5.0 (m, 1H), 4.1 (m, 2H),3.6 (dd, 2H), 3.22 (d, 2H), 2.7-2.9 (m, 3H), 2.6 (m, 1H), 2.4 (s, 3H).Separation by chiral HPLC provides enantiomers II-63a-b.

Example 284 Preparation of Compound Nos. II-64 and II-64a-b

To a solution of2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol(100 mg, 0.325 mmol) in acetonitrile (3 mL), potassium carbonate (135mg, 0.977 mmol) and 2-bromoethanol (61 mg, 0.488 mmol) were added andthe reaction mixture stirred at 60° C. for 1 h. The progress of reactionwas monitored by TLC and LCMS. The reaction mixture was diluted withwater (10 mL) and extracted with EtOAc (3×20 mL). The combined organiclayer was dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by reverse phase HPLC to yield2-[2-(2-hydroxy-ethyl)-8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl]-1-pyridin-4-yl-ethanol.¹H NMR (CD₃OD, formate salt) δ (ppm): 8.41 (d, 2H), 7.38 (d, 2H), 7.2(m, 2H), 6.99 (d, 1H), 5.03 (t, 1H), 4.4 (bs, 2H), 4.3 (d, 2H), 3.93 (t,2H), 3.45-3.62 (m, 2H), 3.2 (m, 2H), 2.9 (m, 2H), 2.4 (s, 3H).Separation by chiral HPLC provides enantiomers II-64a-b.

Example 285 Preparation of Compound Nos. II-65 and II-65a-b

To a solution of2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol(200 mg, 0.651 mmol) in acetonitrile (4 mL), potassium carbonate (270mg, 1.953 mmol) and bromo-acetic acid ethyl ester (163 mg, 0.977 mmol)were added and the reaction mixture was stirred at RT for 1 h. Theprogress of reaction was monitored by TLC and LCMS. The reaction mixturewas diluted with water (10 mL) and extracted with EtOAc (3×30 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andconcentrated to yield[5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-aceticacid ethyl ester (220 mg). To a solution of[5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-aceticacid ethyl ester (120 mg, 0.305 mmol) in ethanol (2 mL), 1N NaOH (3 mL)was added and the reaction mixture stirred at RT for 1 h. The progressof reaction was monitored by LCMS. The reaction mixture was neutralizedwith aq HCl. The solvent was removed under reduced pressure and theresidue diluted with 90% MeOH in DCM and filtered. The filtrate wasconcentrated and residue was purified by reverse phase HPLC to yield[5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-aceticacid. ¹H NMR (CD₃OD, formate salt) δ (ppm): 8.42 (d, 2H), 7.4 (d, 2H),7.2 (d, 2H), 6.9 (d, 1H), 5.03 (t, 1H), 4.6 (bs, 1H), 4.57 (bs, 2H), 4.3(m, 2H), 3.8 (s, 2H), 3.7 (bs, 2H), 3.0 (m, 1H), 2.3 (s, 3H). Separationby chiral HPLC provides enantiomers II-65a-b.

Example 286 Preparation of Compound Nos. II-67 and II-67a-b

To a solution of2-methyl-8-trifluoromethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(1.0 g, 3.70 mmol) in DMF (10 mL) was added sodium hydride (445 mg,11.12 mmol) under nitrogen at 0° C. After stirring for 10 min,4-(oxiran-2-yl)pyridine (806 g, 6.66 mmol) was added dropwise undernitrogen and the reaction mixture was stirred at RT for 12 h. Theprogress of reaction was monitored by TLC and LCMS. The reaction mixturewas poured into ice-cold water and extracted with EtOAc (2×100 mL). Thecombined organic layer was washed with water (5×50 mL) and dried overanhydrous sodium sulfate, concentrated and re-crystallized in diethylether to yield2-(2-methyl-8-trifluoromethoxy-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.58 (d, 2H), 7.17-7.21 (m, 4H), 7.0(d, 1H), 4.6 (m, 1H), 4.0 (m, 2H), 3.38 (dd, 2H), 2.8 (m, 1H), 2.7 (m,2H), 2.6 (m, 1H), 2.18 (s, 3H). Separation by chiral HPLC providesenantiomers II-67a-b.

Example 287 Preparation of Compound Nos. II-68 and II-68a-b

To a solution of8-tert-butyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g,4.1 mmol) in DMF (6 mL) was added sodium hydride (495 mg, 12.3 mmol)under nitrogen at 0° C. and stirred for 10 min. A solution of4-(oxiran-2-yl)pyridine (898 mg, 7.4 mmol) in DMF (2 mL) was addeddropwise into the reaction mixture at RT and stirred for 12 h. Theprogress of reaction was monitored by TLC and LCMS. The reaction masswas poured in ice-cold water and extracted with EtOAc (2×100 mL). Thecombined organic layer was washed with water (5×50 mL), dried overanhydrous sodium sulfate and concentrated. The residue wasre-crystallized with hexane to yield2-(8-tert-butyl-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.7 (d, 2H), 7.3 (s, 1H), 7.2 (d, 1H),7.19 (d, 2H), 7.17 (d, 1H), 4.7 (t, 1H), 4.0 (d, 2H), 3.5 (dd, 2H), 2.82(m, 1H), 2.7 (m, 2H), 2.58 (m, 1H), 2.4 (s, 3H), 1.4 (s, 9H). Separationby chiral HPLC provides enantiomers II-68a-b.

Example 288 Preparation of Compound No. II-70

A solution of2-(pyridin-4-yl)-1-(2,4,4,8-tetramethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol(110 mg) in thionyl chloride (2 mL) was stirred at RT for 20 min. Theexcess thionyl chloride was removed under reduced pressure, and to theresidue were added DMF (2 mL) and powdered KOH (140 mg, 0.303 mmol),followed by stirring at 85° C. for 25 min. The progress of reaction wasmonitored by LCMS. The reaction mixture was diluted with water (50 mL)and extracted with EtOAc (3×30 mL). The organic layer was washed withwater (2×20 mL), dried over anhydrous sodium sulfate and evaporated toafford crude material, which was purified by reverse phase HPLC. ¹H NMR(CD₃OD, TFA salt) δ (ppm): 8.7 (d, 2H), 8.0 (d, 2H), 7.58 (s, 1H), 7.37(s, 1H), 7.1 (d, 1H), 7.05 (d, 1H), 4.7 (bs, 1H), 4.4 (bs, 1H), 3.5 (d,2H), 3.18 (s, 3H), 2.42 (s, 3H), 1.97 (s, 3H), 1.57 (bs, 6H).

Example 289 Preparation of Compound Nos. II-71 and II-71a-b

To a solution of9-chloro-2-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (1 g, 4.273mmol) in DMF was added NaH (512 mg, 12.81 mmol) in portions at 0° C.After stirring the reaction mixture at 0° C. for 15 min, a solution of4-(oxiran-2-yl)pyridine (775 mg, 6.409 mmol) in DMF (1 mL) was addeddropwise into the mixture at the same temperature and stirring continuedat RT overnight. The progress of reaction was monitored by TLC and LCMS.After completion, ice water was added into the reaction mixture andextracted with EtOAc (3×50 mL). The organic layer was washed with water(5×50 mL), dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by silica gel column chromatography using 10%MeOH/DCM as eluent followed by recrystallization with MeOH andacetonitrile to yield2-(9-chloro-2-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-6(1H)-yl)-1-(pyridin-4-yl)ethanol.¹H NMR (CDCl₃, Free base) δ (ppm): 8.5 (d, 2H), 7.4 (s, 1H), 7.3 (d,2H), 7.19 (d, 1H), 7.05 (d, 1H), 4.85 (dd, 1H), 4.18 (m, 2H), 3.8 (d,1H), 3.65 (d, 1H), 3.0 (m, 2H), 2.8 (m, 1H), 2.69 (m, 1H), 2.42 (s, 3H),1.85 (m, 2H). Separation by chiral HPLC provides enantiomers II-71a-b.

Example 290 Preparation of Compound Nos. II-75 and II-75a-b

To a solution of3-(3,4-dihydro-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)propan-1-ol (1000mg, 4.0983 mmol) in DMF (10 mL) was portionwise added sodium hydride(491.8 mg, 12.25 mmol). After stirring at RT for 5 min,4-(oxiran-2-yl)pyridine (620 mg, 4.92 mmol) was added dropwise into thereaction mixture, which was stirred at RT overnight. Ice water was addedinto the reaction mixture and the solid mass filtered, washed with water(2×10 mL) and hexane (2×50 mL). The residue was purified by reversephase HPLC to yield3-(3,4-dihydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)propan-1-ol.¹H NMR (CD₃OD, formate salt) δ (ppm): 8.43 (bs, 2H), 7.39 (d, 2H), 7.23(s, 1H), 7.2 (d, 1H), 7.0 (d, 1H), 5.07 (t, 1H), 4.48 (bs, 2H), 4.23 (m,2H), 3.7 (t, 2H), 3.6 (bs, 2H), 3.4 (t, 2H), 3.2 (m, 1H), 2.95-3.03 (m,1H), 2.4 (s, 3H), 2.03 (bs, 2H). Separation by chiral HPLC providesenantiomers II-75a-b.

Example 291 Preparation of Compound No. II-76

To a de-aerated solution of(E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yltrifluoromethanesulfonate (200 mg, 0.515 mmol),4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (225mg, 1.03 mmol) and K₂CO₃ (215 mg, 1.55 mmol) in DME (2 mL) and water (1mL) was added Pd(PPh₃)₄ (52 mg, 0.045 mmol). The reaction mixture wasstirred at 90° C. for 45 min. The solvent was removed under reducedpressure, and the residue was diluted with water and extracted withEtOAc. The organic layer was dried over anhydrous sodium sulfate andevaporated to afford crude material, which was purified by reverse phaseHPLC to yield(E)-2,8-dimethyl-5-(2-(4-methylpyridin-3-yl)prop-1-en-1-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoleas the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.87 (s, 1H), 8.75(d, 1H), 8.0 (d, 1H), 7.3 (s, 1H), 7.24 (d, 1H), 7.17 (d, 1H), 6.8 (s,1H), 4.77 (d, 1H), 4.38 (d, 1H), 3.9 (bs, 1H), 3.4 (bs, 1H), 3.3 (m,1H), 3.18 (m, 1H), 3.12 (s, 3H), 2.8 (s, 3H), 2.42 (s, 3H), 2.0 (s, 3H).

Example 292 Preparation of Compound No. II-77

To a degassed solution of2,8-dimethyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-1-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(200 mg, 0.546 mmol), 5-bromo-2-ethylpyridine (50 mg, 0.273 mmol) andK₂CO₃ (113 mg, 0.819 mmol) in DME (2 mL) and water (1 mL) was addedPd(PPh₃)₄ (22 mg, 0.019 mmol). The reaction mixture was purged withnitrogen and heated to reflux for 45 min. The reaction mixture wascooled to RT, diluted with water and extracted with EtOAc (3×6 mL). Thecombined organic layer was dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure to afford crude product whichwas purified by reverse phase HPLC as a TFA salt. ¹H NMR (CD₃OD, TFAsalt) δ (ppm): 8.98 (s, 1H), 8.78 (d, 1H), 8.0 (d, 1H), 7.38 (d, 2H),7.18 (d, 1H), 7.1 (d, 1H), 4.76 (d, 1H), 4.4 (d, 1H), 3.85 (bs, 1H), 3.6(bs, 1H), 3.2 (m, 2H), 3.18 (s, 3H), 3.1 (s, 2H), 2.64 (s, 3H), 2.05 (s,3H), 1.5 (t, 3H).

Example 293 Preparation of Compound Nos. II-78 and II-78a-b

To a solution of 6-methyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene(1.0 g, 0.0053 mole) in DMF (15 mL) were added portionwise NaH (60%,0.634 g, 0.0159 mole) and 4-(oxiran-2-yl)pyridine (0.807 g, 0.0064mole). The reaction mixture was stirred at RT overnight. The progress ofreaction was monitored by LCMS. The reaction mixture was quenched withice cold water (300 mL) and extracted with EtOAc (3×100 mL). Thecombined organic layer was washed with water (10×100 mL), brine (2×100mL), dried over anhydrous sodium sulfate and concentrated. The residuewas purified by silica gel column chromatography followed by reversephase HPLC to yield the title compound. ¹H NMR (CDCl₃, freebase) δ(ppm): 8.5 (d, 2H), 8.2 (d, 1H), 7.7 (d, 1H), 7.23 (d, 2H), 7.9 (m, 1H),5.08 (m, 1H), 4.5 (d, 1H), 4.3 (d, 1H), 3.6 (dd, 2H), 2.9 (m, 1H), 2.8(m, 1H), 2.7 (m, 1H), 2.6 (m, 1H), 2.5 (s, 3H). Separation by chiralHPLC provides enantiomers II-78a-b.

Example 294 Preparation of Compound Nos. II-80 and II-80a-b

A solution of1-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-(6-methoxy-pyridin-3-yl)-propan-2-ol(100 mg, 0.27 mmol) in 3N HCl (4 mL) was stirred at 100° C. for 4 h. Thereaction mixture was concentrated under reduced pressure and the residuewas purified by reverse phase HPLC to yield5-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-1-methyl-ethyl]-pyridin-2-ol.¹H NMR (CD₃OD, freebase) δ (ppm): 7.58 (d, 1H), 7.2 (s, 1H), 7.1 (s,1H), 7.0 (d, 1H), 6.8 (d, 1H), 6.4 (d, 1H), 4.6 (bs, 1H), 4.17 (m, 2H),4.0 (m, 2H), 3.1-3.25 (m, 2H), 2.97 (m, 1H), 2.8 (s, 3H), 2.4 (s, 3H),1.6 (s, 3H). Separation by chiral HPLC provides enantiomers II-80a-b.

Example 295 Preparation of Compound Nos. II-81 and II-81a-b

To a solution of5-(2-hydroxy-2-pyridin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylicacid ethyl ester (200 mg, 0.547 mmol) in dry THF (10 mL) was addedportionwise LAH (63 mg, 1.65 mmol) under nitrogen at RT. After stirringfor 2 h, the reaction mixture was quenched with water (0.5 mL), NaOH (1mL). The organic layer was separated and concentrated under reducedpressure. The crude product was purified by reverse phase chromatographyto yield2-(8-hydroxymethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol.¹H NMR (CD₃OD, freebase) δ (ppm): 8.41 (d, 2H), 7.42 (s, 1H), 7.39 (d,2H), 7.3 (d, 1H), 7.19 (d, 1H), 5.08 (t, 1H), 4.66 (s, 2H), 4.4 (s, 2H),4.3 (m, 2H), 3.5 (m, 2H), 3.2 (m, 1H), 2.9 (m, 1H). Separation by chiralHPLC provides enantiomers II-81a-b.

Example 296 Preparation of Compound No. II-82

5-(2-Bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.29 mmol),2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (127mg, 0.58 mmol) and K₂CO₃ (120 mg, 0.87 mmol) were mixed in1,2-dimethoxyethane (4 mL) and water (2 mL). The reaction mixture waspurged with nitrogen, Pd(PPh₃)₄ (17 mg, 0.0147 mmol) was added and thereaction mixture was heated at 90° C. for 45 min. The reaction mixturewas cooled to RT and concentrated under reduced pressure. The residuewas diluted with water (20 mL) and extracted with EtOAc (50 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by reverse phase HPLCto yield 26 mg of2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoleas the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.0 (d, 1H), 7.8 (dd,1H), 7.61 (d, 1H), 7.31 (s, 1H), 6.95-7.10 (m, 2H), 4.7 (d, 1H), 4.38(d, 1H), 3.8 (m, 1H), 3.55 (m, 1H), 2.82-3.2 (m, 9H), 2.61 (s, 3H), 2.4(s, 3H), 2.3 (m, 2H).

Example 297 Preparation of Compound Nos. II-83 and II-83a-d

To a solution of2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol(200 mg, 0.651 mmol) in acetonitrile (4 mL), potassium carbonate (270mg, 1.95 mmol) and 1-bromopropan-2-ol (135 mg, 0.977 mmol) were addedand stirred the reaction mixture at 100° C. for 2 h. The reactionmixture was diluted with water (10 mL) and extracted with EtOAc (3×20mL). The combined organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified byreverse phase HPLC to yield1-[5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-propan-2-ol.¹H NMR, (CDCl₃, freebase) δ (ppm): 8.58 (s, 2H), 7.36 (m, 2H), 7.2 (m,2H), 7.02 (d, 1H), 5.1 (s, 1H), 4.3 (m, 1H), 4.1 (m, 2H), 4.0 (m, 2H),3.56 (m, 1H), 3.37 (m, 1H), 3.1-3.3 (m, 2H), 2.8 (m, 2H), 2.42 (s, 3H),1.2 (d, 3H). Separation by chiral HPLC provides diastereomers II-83a-d.

Example 298 Preparation of Compound Nos. II-84 and II-84a-b

To a solution of2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol(200 mg, 0.651 mmol) in acetonitrile (4 mL), potassium carbonate (270mg, 1.95 mmol) and 1-chloro-2-methyl-propan-2-ol (105 mg, 0.977 mmol)were added and the reaction mixture was stirred at 100° C. for 12 h. Thereaction mixture was diluted with water (10 mL) and extracted with EtOAc(3×20 mL). The combined organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by column chromatography (Neutral alumina, 1% MeOH-DCM), toyield1-[5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-2-methyl-propan-2-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.6 (d, 2H), 7.27 (m, 2H), 7.2 (m,2H), 7.0 (d, 1H), 5.08 (t, 1H), 4.19 (m, 2H), 3.9 (bs, 2H), 3.0-3.1 (m,2H), 2.9 (m, 1H), 2.6 (s, 2H), 2.56 (m, 1H), 2.21 (s, 3H), 1.21 (s, 6H).Separation by chiral HPLC provides enantiomers II-84a-b.

Example 299 Preparation of Compound Nos. II-88 and II-88a-b

To a solution of1-(3,4-Bis-allyloxy-phenyl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanol(500 mg, 1.15 mmol) in 10 mL MeOH was purged with nitrogen for 10 min.1,3-Dimethylbarbituric acid (903 mg, 5.79 mmol) and Pd(PPh₃)₄ (80 mg,0.069 mmol) were added under nitrogen and the mixture stirred for 30 minat RT. After the complete conversion of starting material (TLC andLCMS), the MeOH was removed under reduced pressure. 100 mL of saturatedsodium bicarbonate was added and the mixture was extracted with EtOAc(3×100 mL). The combined organic layers were dried over anhydrous sodiumsulfate and concentrated. The resultant crude product was purified byHPLC to obtain 160 mg of4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzene-1,2-diol.¹H NMR (CD₃OD, Free base) δ (ppm): 7.3 (d, 1H), 7.2 (s, 1H), 7.05 (dd,1H), 6.7 (d, 1H), 6.6 (s, 1H), 6.53 (d, 1H), 4.8 (t, 1H), 4.21 (m, 3H),4.05 (dd, 1H), 3.34 (m, 1H), 3.3 (m, 1H), 2.88 (dt, 1H), 2.81 (s, 3H),2.5 (dt, 1H), 2.4 (s, 3H). Separation by chiral HPLC providesenantiomers II-88a-b.

Example 300 Preparation of Compound Nos. II-89 and II-89a-b

To a degassed solution of2-(2-allyl-8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-3-yl-ethanol(1.0 g, 2.7 mmol) in DCM were added 1,3-dimethyl barbituric acid (1.27g, 8.1 mmol) and Pd(PPh₃)₄ (63 mg, 0.054 mmol) and the reaction mixturewas stirred at RT for 3 h. The solvent was removed under reducedpressure. The residue was dissolved in saturated potassium carbonatesolution and extracted with EtOAc (3×50 mL). The combined organic layerwas washed with saturated potassium carbonate (6×20 mL), dried overanhydrous sodium sulfate and concentrated. The residue was purified bycolumn chromatography (neutral alumina, 20% methanol in DCM) followed byreverse phase HPLC to yield2-(8-chloro-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-3-yl-ethanol.¹H NMR (CD₃OD, freebase) δ (ppm): 8.4 (d, 1H), 8.37 (s, 1H), 7.8 (d,1H), 7.4 (d, 1H), 7.39 (m, 1H), 7.2 (d, 1H), 7.02 (d, 1H), 5.1 (t, 1H),4.33 (d, 2H), 4.3 (s, 2H), 3.38-3.5 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H).Separation by chiral HPLC provides enantiomers II-89a-b.

Example 301 Preparation of Compound Nos. II-90 and II-90a-b

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(300 mg, 1.5 mmol) in DMF (5 mL) was added sodium hydride (180 mg, 4.5mmol) under nitrogen. After stirring at RT for 10 min,4-(oxiran-2-yl)quinoline (384 mg, 2.25 mmol) was added dropwise undernitrogen into the reaction mixture, which was stirred at RT for 18 h.The progress of reaction was monitored by TLC, LCMS and NMR. Thereaction mixture was poured in ice-cold water and extracted with EtOAc(2×50 mL). The combined organic layer was washed with water (3×50 mL),dried over anhydrous sodium sulfate and concentrated under reducedpressure. Re-crystallization with diethyl ether yielded2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(quinolin-4-yl)ethanol(140 mg). ¹H NMR (CDCl₃, freebase) δ (ppm): 8.86 (d, 1H), 8.19 (d, 1H),7.97 (d, 1H), 7.78 (t, 1H), 7.41 (d, 1H), 7.56 (t, 1H), 7.2 (d, 1H),6.93-7.01 (m, 2H), 5.57 (t, 1H), 4.2 (dd, 1H), 4.1 (dd, 1H), 3.37 (dd,2H), 2.83 (m, 1H), 2.71 (bs, 3H), 2.4 (s, 3H), 2.38 (s, 3H). Separationby chiral HPLC provides enantiomers II-90a-b.

Example 302 Preparation of Compound Nos. II-91 and II-91a-b

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(525 mg, 2.6 mmol) in DMF was added sodium hydride (312 mg, 7.8 mmol) at0° C. After stirring the solution for 15 min, a solution of2-cyclohexyloxirane (500 mg, 3.9 mmol) was added dropwise into thereaction mixture, which was stirred at RT overnight. The progress ofreaction was monitored by TLC, NMR and LCMS. The reaction mixture wasquenched with ice-cold water and extracted with EtOAc. The organic layerwas thoroughly washed with water, dried over anhydrous sodium sulfateand concentrated. Re-crystallization with ether yielded the desiredproduct (160 mg). ¹H NMR (CDCl₃, Free base) δ (ppm): 7.2 (s, 1H), 7.19(d, 1H), 6.95 (d, 1H), 4.15 (dd, 1H), 3.92 (dd, 1H), 3.7 (m, 1H), 3.6(s, 2H), 2.99 (m, 1H), 2.8 (m, 3H), 2.58 (s, 3H), 2.42 (s, 3H), 1.9 (d,1H), 1.8 (m, 2H), 1.7 (d, 2H), 1.52 (m, 1H), 1.22 (m, 5H). Separation bychiral HPLC provides enantiomers II-91a-b.

Example 303 Preparation of Compound No. II-92 and II-92a-b

A solution of2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(6-methoxy-pyridin-3-yl)-ethanol(200 mg, 0.569 mmol) in 3N HCl (8 mL) was stirred at 100° C. for 3 h.The reaction mixture was concentrated under reduced pressure and residuewas purified by reverse phase HPLC to yield5-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-hydroxyethyl)pyridin-2(1H)-one.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.5 (m, 1H), 7.23 (s, 1H), 7.2 (s,1H), 7.19 (d, 1H), 6.5 (s, 1H), 4.62 (d, 1H), 4.19-4.37 (m, 3H), 3.8 (m,1H), 3.5 (m, 1H), 3.24 (m, 2H), 3.1 (m, 4H), 2.4 (s, 3H). Separation bychiral HPLC provides enantiomers II-92a-b.

Example 304 Preparation of Compound Nos. II-93 and II-93a-b

To a solution of2-(8-chloro-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol(600 mg, 1.84 mmol) in acetone (20 mL) were added 2-bromoethanol (341mg, 2.76 mmol) and K₂CO₃ (761 mg, 5.52 mmol) and the reaction mixturestirred at 80° C. for 4 h. The progress of reaction was monitored by TLCand LCMS. The reaction mixture was cooled to RT, filtered and thefiltrate concentrated under reduced pressure. The residue was dilutedwith water and extracted with EtOAc. The organic layer was dried overanhydrous sodium sulfate and concentrated. The residue was purified byreverse phase HPLC to yield the title compound. ¹H NMR (CDCl₃, Freebase) δ (ppm): 8.41 (d, 2H), 7.31 (s, 1H), 7.18 (m, 4H), 4.79 (t, 1H),4.0 (m, 2H), 3.68 (m, 3H), 3.56 (d, 1H), 2.8 (m, 3H), 2.65 (m, 2H), 2.58(m, 1H). Separation by chiral HPLC provided enantiomers II-93a-b.

Example 305 Preparation of Compound Nos. II-94 and II-94a-b

To a solution of2-(8-chloro-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-(pyridin-3-yl)ethanol(1.0 g, 3.05 mmol) in acetone (30 mL) were added 2-bromoethanol (758 mg,6.12 mmol) and K₂CO₃ (1.3 g, 9.43 mmol) and the reaction mixture stirredat 80° C. for 4 h. The progress of reaction was monitored by TLC andLCMS. The reaction mixture was cooled to RT, filtered and the filtrateconcentrated under reduced pressure. The residue was diluted with waterand extracted with EtOAc. The organic layer was dried over anhydroussodium sulfate and concentrated. The residue was purified by reversephase HPLC to yield the title compound. ¹H NMR (CDCl₃, Free base) δ(ppm): 8.39 (d, 1H), 8.2 (s, 1H), 7.6 (d, 1H), 7.27 (s, 1H), 7.2 (m,2H), 7.16 (d, 1H), 4.8 (m, 1H), 4.1 (dd, 1H), 4.0 (dd, 1H), 3.7 (m, 2H),3.6 (d, 1H), 3.5 (d, 1H), 2.85 (m, 3H), 2.8 (m, 1H), 2.63 (m, 2H).Separation by chiral HPLC provided enantiomers II-94a-b.

Example 306 Preparation of Compound Nos. II-95 and II-95a-d

Phenyl magnesium bromide (1M solution in THF) (6.24 mL, 6.24 mmol) wasadded dropwise at −70° C. to a stirred solution of2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-propionaldehyde(400 mg, 1.56 mmol) in THF (40 mL), the reaction mixture stirred at RTfor 16 h, diluted with EtOAc (75 mL) and water (60 mL). The two layerswere separated, the aq. layer extracted with EtOAc (2×75 mL), and thecombined organic layers dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crude (500 mg) was purified byprep. HPLC to afford2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)1-phenyl-propan-1-ol yielded as the TFA salt (65 mg). ¹H NMR (CDCl₃,Free base) δ (ppm): 7.37 (d, 1H), 7.17 (t, 3H), 7.12 (s, 1H), 7.06 (m,2H), 6.95 (d, 1H), 5.11 (t, 1H), 4.37 (t, 1H), 3.57 (dd, 1H), 3.46 (d,1H), 2.67 (m, 2H), 2.51 (m, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 1.68 (d,3H). Separation by chiral HPLC provides diastereomers II-95a-d.

Example 307 Preparation of Compound No. II-96

To a solution of 1-(2,8-dimethyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5(2h)-yl)prop-1-en-2-yltrifluoromethanesulfonate(100 mg, 0.257 mmol) in DME (4 mL) was added Pd(PPh₃)₄ (15 mg, 0.0128)and the reaction mixture was purged with N₂. 2-Fluoropyridine-5-boronicacid pinacol ester (115 mg, 0.515 mmol), K₂CO₃ (36 mg, 0.257 mmol) andwater (2 mL) were added, the reaction mixture was purged with nitrogenand refluxed for 45 min. The reaction mixture was cooled to RT, and thesolvent was removed under reduced pressure. The residue was dissolved inwater, extracted with EtOAc, washed with brine, and concentrated toafford crude product which was purified by silica gel chromatographyfollowed by reverse phase HPLC to obtain the products as TFA salts. ¹HNMR (CD₃OD, TFA salt) δ (ppm): 8.42 (s, 1H), 8.21 (m, 1H), 7.28 (s, 1H),7.02-7.21 (m, 4H), 4.78 (d, 1H), 4.40 (d, 1H), 3.82 (m, 1H), 3.58 (m,1H), 3.16 (m, 5H), 2.41 (s, 3H), 2.0 (s, 3H).

Example 308 Preparation of Compound Nos. II-97 and II-97a-b

To a solution of2-(1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanol(200 mg, 0.652 mmol) and sodium 2-bromoethanesulfonate (164 mg, 0.78mmol) in DMF (3 mL) and water (0.5 mL), were added sodium bicarbonate(164 mg, 1.95 mmol) and potassium iodide (128 mg, 0.78 mmol) and thereaction mixture was stirred at 90° C. for 2 h. The reaction mixture wasdiluted with water and extracted with DCM. The aqueous layer wasneutralized with aq HCl and the solid obtained was recrystallized fromMeOH to yield2-(3,4-dihydro-5-(2-hydroxy-2-(pyridin-4-yl)ethyl)-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)ethanesulfonicacid as a white solid (80 mg). ¹H NMR (CD₃OD, Free base) δ (ppm): 8.45(d, 2H), 7.40 (d, 2H), 7.26 (s, 1H), 7.23 (d, 1H), 7.00 (s, 1H), 5.06(t, 1H), 4.59 (m, 2H), 4.29 (m, 2H), 3.71 (t, 4H), 3.55 (m, 2H), 3.0 (d,1H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomersII-97a-b.

Example 309 Preparation of Compound No. II-98 and II-98a-d

To an ice-cooled stirred suspension of 4-bromopyridine hydrochloridesalt (1.0 g, 5.1 mmol) in THF (5 mL) was added isopropyl magnesiumchloride (2M in THF, 5 mL, 10.3 mmol) and stirred the reaction at RT for30 min. A solution of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanal (300mg, 1.17 mmol) in THF (3 mL) was added into the brown colored reactionmixture, which was stirred at RT for 1.5 h. The progress of reaction wasmonitored by TLC and LCMS (45% conversion). The reaction mixture wascooled to 0° C. and quenched with cold saturated ammonium chloridesolution (till effervescence stopped) and water was added, stirred at RTfor 15 min and extracted with EtOAc. The organic layer was dried overanhydrous sodium sulfate and evaporated. The residue was purified byreverse phase HPLC. ¹H NMR (CDCl₃, Free base) δ (ppm): 8.60 (d, 2H), 7.4(d, 1H), 7.55 (d, 2H), 7.18 (s, 1H), 6.98 (d, 1H), 5.15 (d, 1H), 4.2 (t,1H), 3.4 (d, 1H), 3.28 (d, 1H), 2.94 (m, 1H), 2.784 (m, 1H), 2.68 (m,2H), 2.48 (s, 3H), 2.43 (s, 3H), 1.37 (s, 3H). Separation by chiral HPLCprovides diastereomers II-98a-d.

Example 310 Preparation of Compound Nos. II-99 and II-99a-b

To a solution of 6-aza-2,8-dimethyl carboline (500 mg, 2.5 mmol) in DMF(5 mL) was added NaH (60%, 300 mg, 7.5 mmol). After stirring for 5 minat RT, a solution of 3-(2-methyloxiran-2-yl)pyridine (506.2 mmol, 3.75mmol) in DMF (1 mL) was added dropwise into the reaction mixture, whichwas stirred at RT for 12 h. The progress of reaction was monitored byTLC and LCMS. The reaction mixture was quenched with ice-water andextracted with EtOAc. The organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was triturated with ether to yield the desired compound (150mg). ¹H NMR (CDCl₃, Free base) δ (ppm): 8.7 (s, 1H), 8.41 (d, 1H), 8.02(s, 1H), 7.8 (d, 1H), 7.5 (s, 1H), 7.19 (dd, 1H), 4.3 (dd, 2H), 3.6 (d,1H), 3.5 (d, 1H), 2.8 (m, 2H), 2.65 (m, 1H), 2.55 (s, 3H), 2.49 (m, 1H),2.4 (s, 3H), 1.6 (s, 3H). Separation by chiral HPLC provided enantiomersII-99a-b.

Example 311 Preparation of Compound Nos. II-100 and II-100a-b

Aza-dimethyl-carboline (100 mg, 0.497 mmol) was charged in a reactionbottle and N,N-dimethylformamide (2 mL) was added. Sodium hydride (60%suspension in mineral oil) (60 mg, 1.49 mmol) was added portionwise. Thereaction mixture was stirred at RT for 5 min and2-methyl-5-(oxiran-2-yl)pyridine (300 mg, 2.22 mmol) was added dropwise.The reaction mixture was stirred at RT overnight. The reaction wasmonitored by LCMS. Ice water (5 mL) was added and the organic layer wasextracted with EtOAc (2×15 mL). The combined organic layer was washedwith water (3×5 mL) and concentrated. The desired product was purifiedthrough reverse phase chromatography as a racemate (12.92 mg). ¹H NMR(CDCl₃, Free base) δ (ppm): 8.42 (s, 1H), 8.0 (s, 1H), 7.5 (s, 1H), 7.47(d, 1H), 7.07 (d, 1H), 5.1 (m, 1H), 4.37 (dd, 1H), 4.26 (dd, 1H), 3.59(dd, 2H), 2.78 (m, 1H), 2.7 (m, 2H), 2.52 (s, 3H), 2.5 (s, 3H), 2.45 (m,1H), 2.42 (s, 3H). Separation by chiral HPLC provided enantiomersII-100a-b.

Example 312 Preparation of Compound No. II-101

2,8-Dimethyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-pyrido[4,3-b]indol-1-one(350 mg, 1.057 mmol) was dissolved in dry toluene (6 mL). Methylmagnesium bromide (3M solution in diethyl ether, 1.76 mL, 5.28 mmol) wasadded and the reaction mixture was heated at 100° C. for 1 h. Thereaction mixture was cooled to RT, quenched with ice water and filteredthrough a Celite bed. The filtrate was extracted with EtOAc (3×70 mL).The combined organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography over neutral alumina followed by reverse phase HPLC toobtain 6.5 mg of1,1,2,8-tetramethyl-5-(2-pyridin-4-yl-propenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoleas a formate salt. ¹H NMR (CD₃OD, formate salt) δ (ppm): 8.60 (d, 2H),7.70 (d, 2H), 7.50 (s, 1H), 7.30 (s, 1H), 7.12 (m, 2H), 3.70 (t, 2H),3.10 (t, 2H), 3.02 (s, 3H), 2.44 (s, 3H), 2.02 (s, 3H), 1.90 (s, 6H).

Example 313 Preparation of Compound Nos. II-102 and II-102a-b

To a solution of methyl carboline ethyl ester (500 mg, 1.27 mmol) in THF(30 mL) was added LAH (145 mg, 3.81 mmol) under nitrogen at RT andstirred for 1 h. The progress of reaction was monitored by TLC and LCMS.The reaction mixture was quenched by adding water (0.5 mL), 1N NaOH (1mL) and water (0.5 mL). The inorganic material was removed by filtrationand the filtrate concentrated under reduced pressure. The residue wastriturated with ether to yield the title compound (450 mg). ¹H NMR(CD₃OD, Free base) δ (ppm): 8.5 (s, 1H), 8.39 (d, 1H), 7.8 (d, 1H), 7.26(m, 2H), 7.1 (d, 1H), 7.0 (d, 1H), 4.6 (s, 2H), 4.21 (q, 2H), 3.62 (s,2H), 2.79 (m, 4H), 2.49 (s, 3H), 1.64 (s, 3H). Separation by chiral HPLCprovides enantiomers II-102a-b.

Example 314 Preparation of Compound No. II-103

To a stirred solution of6-methyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (200 mg,1.068 mmol) in NMP (3 mL) was added powdered KOH (419 mg, 7.486 mmol).After stirring for 10 min at RT, 2-(trifluoromethyl)-5-vinylpyridine(370 mg, 2.14 mmol) was added to the reaction mixture and stirringcontinued for another 3 h. The progress of reaction was monitored by TLCand NMR. The reaction mixture was diluted with water (20 mL) andextracted with EtOAc (3×20 mL). The organic layer was washed with water(5×20 mL), dried over anhydrous sodium sulfate and concentrated underreduced pressure to afford crude material, which was purified by reversephase HPLC to yield6-methyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridineas the TFA salt (100 mg). ¹H NMR (CDCl₃, TFA salt) δ (ppm): 8.4 (s, 1H),8.2 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 7.4 (d, 1H), 7.0 (s, 1H), 4.4 (s,2H), 3.6 (s, 2H), 3.2 (s, 2H), 2.78 (s, 2H), 2.6 (s, 2H), 2.5 (s, 3H).

Example 315 Preparation of Compound Nos. II-104 and II-104a-b

To a solution of methyl carboline ethyl ester (350 mg, 0.92 mmol) in THF(5 mL) was added LAH (175 mg, 4.6 mmol) under nitrogen at RT and stirredfor 1 h. The progress of reaction was monitored by TLC and LCMS. Thereaction mixture was quenched by adding water (0.5 mL), 1N NaOH (1 mL)and water (0.5 mL). The inorganic material was removed by filtration,and the filtrate concentrated under reduced pressure. The residue waspurified through reverse phase HPLC to yield the title compound. ¹H NMR(CD₃OD, Free base) δ (ppm): 8.5 (s, 1H), 8.3 (d, 1H), 7.82 (d, 1H), 7.4(s, 1H), 7.3 (dd, 1H), 7.0 (m, 2H), 4.6 (s, 2H), 4.4 (dd, 2H), 4.41 (d,1H), 4.2 (d, 1H), 3.5 (m, 2H), 3.21 (m, 1H), 3.0 (m, 1H), 1.64 (s, 3H).Separation by chiral HPLC provides enantiomers II-104a-b.

Example 316 Preparation of Compound Nos. II-105 and II-105a-b

1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol(500 mg, 1.49 mmol) was dissolved in 10 mL DCM and m-chloro perbenzoicacid (383 mg, 2.24 mmol) was added and the mixture stirred at RT. Afterconsumption of starting material by monitoring TLC and LCMS, thereaction mixture was concentrated and the crude product was purified byreverse phase chromatography, to obtain 110 mg of1-(2,8-dimethyl-2-oxy-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol.¹H NMR (CDCl₃, Free base) δ (ppm): 8.7 (s, 1H), 8.25 (d, 1H), 7.8 (d,1H), 7.4 (bs, 1H), 7.27 (d, 1H), 7.2 (m, 2H), 7.0 (d, 1H), 4.79 (d, 1H),4.6 (d, 1H), 4.2 (d, 1H), 4.05 (d, 1H), 3.85 (m, 1H), 3.6 (m, 1H), 3.4(m, 1H), 2.64 (m, 1H), 2.4 (s, 3H), 1.6 (s, 3H). Separation by chiralHPLC provides enantiomers II-105a-b.

Example 317 Preparation of Compound Nos. II-106 and II-106a-b

1-(1-(1-Ethoxyethyl)-1H-pyrazol-4-yl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanol(147 mg, 0.3848 mmol) was dissolved in 1,4-dioxane (15 mL) and to it wasadded 20% aqueous hydrochloride solution (15 mL). The mixture was heatedat 55° C. for 1 h. The reaction mixture was neutralized with a saturatedsolution of sodium bicarbonate and was extracted with EtOAc (3×60 mL).The combined organic layer was washed with water (15 mL) and then brine(2×30 mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crude product was purified byreverse phase chromatography. Yield: 36.6 mg (TFA salt). ¹H NMR (CDCl₃,Free base) δ (ppm): 7.35 (s, 1H), 7.0 (s, 1H), 6.9 (d, 1H), 6.8 (d, 1H),6.2 (s, 1H), 4.9 (t, 1H), 4.2 (dd, 2H), 3.55 (d, 1H), 3.4 (d, 1H), 2.8(m, 2H), 2.6 (m, 2H), 2.5 (s, 3H), 2.39 (s, 3H). Separation by chiralHPLC provided enantiomers II-106a-b.

Example 318 Preparation of Compound Nos. II-108 and II-108a-b

To a solution of dimethyl-aza carboline (400 mg, 1.99 mmol) in DMF (5mL) was added NaH (239 mg, 5.97 mmol, 60%). After stirring at RT for 10min, the epoxide (606 mg, 2.98 mmol) was added into the reactionmixture, which was stirred at RT for 16 h. The progress of reaction wasmonitored by TLC and LCMS. The reaction mixture was quenched withice-water and extracted with EtOAc. The organic layer was washed withwater, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The product was re-crystallized from ether (250 mg).¹H NMR (CDCl₃, Free base) δ (ppm): 8.81 (s, 1H), 8.0 (m, 2H), 7.6 (d,1H), 7.52 (s, 1H), 4.23 (q, 2H), 3.6 (d, 1H), 3.5 (d, 1H), 2.8 (m, 1H),2.72 (m, 3H), 2.5 (s, 3H), 2.4 (m, 1H), 2.4 (s, 3H), 1.6 (s, 3H).Separation by chiral HPLC provided enantiomers II-108a-b.

Example 319 Preparation of Compound Nos. II-109 and II-109a-b

To a solution of6-aza-8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (400mg, 1.8 mmol) in DMF (5 mL) was added NaH (217 mg, 5.42 mmol, 60%).After stirring at RT for 10 min, the epoxide (552 mg, 2.71 mmol) wasadded into the reaction mixture, which was stirred at RT for 16 h. Theprogress of reaction was monitored by TLC and LCMS. The reaction mixturewas quenched with ice-water and extracted with EtOAc. The organic layerwas washed with water, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The product was re-crystallizedfrom ether (340 mg). ¹H NMR (CDCl₃, Free base) δ (ppm): 8.8 (s, 1H),8.15 (s, 1H), 8.0 (d, 1H), 7.68 (s, 1H), 7.6 (d, 1H), 4.23 (q, 2H), 3.6(d, 1H), 3.5 (d, 1H), 2.8 (m, 3H), 2.72 (m, 1H), 2.5 (s, 3H), 2.4 (m,1H), 1.6 (s, 3H). Separation by chiral HPLC provided enantiomersII-109a-b.

Example 320 Preparation of Compound No. II-110

To a solution of3,6-dimethyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (201mg, 1.0 mmol) in DMF (1 mL) was added a suspension of NaH (128.0 mg,3.24 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (873 mg, 3.0mmol) in DMF (1 mL) was added dropwise into the reaction mixture andstirring continued for another 3 h. The progress of reaction wasmonitored by TLC and NMR. The reaction mixture was diluted with water(20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washedwith water (3×20 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude material, which waspurified by silica gel flash chromatography and 10% MeOH-DCM to yield3,6-dimethyl-9-(2-(6-methylpyridin-3-yl)ethyl)-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine(190 mg). ¹H NMR (CDCl₃, TFA salt) δ (ppm): 8.2 (s, 1H), 8.04 (s, 1H),7.43 (s, 1H), 7.18 (d, 1H), 7.0 (d, 1H), 4.3 (t, 2H), 3.6 (s, 2H), 3.0(t, 2H), 2.7 (t, 2H), 2.5 (s, 8H), 2.4 (s, 3H).

Example 321 Preparation of Compound Nos. II-111 and II-111a-b

5-[2-(3,6-Dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile(600 mg, 1.729 mmol) was dissolved in tert-butanol (12 mL), crushedpotassium hydroxide (290 mg, 5.187 mmol) was added, and the mixtureheated at 80° C. for 1 h. The reaction was monitored by TLC & LCMS. Thereaction mixture was allowed to cool to RT, the solvent was removedunder vacuum, and the residue was diluted with water (20 ml) andextracted with EtOAc (2×75 mL). The combined organic layer was driedover anhydrous sodium sulfate and concentrated to obtain the crudeproduct that was purified by reverse phase chromatography to afford 100mg of5-[2-(3,6-dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-hydroxy-ethyl]-pyridine-2-carboxylicacid amide. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.62 (s, 1H), 8.1 (s, 1H),8.05 (d, 1H), 7.95 (d, 1H), 7.8 (s, 1H), 5.23 (t, 1H), 4.7 (d, 1H), 4.53(d, 1H), 4.4 (m, 2H), 3.83 (m, 1H), 3.6 (m, 1H), 3.4 (m, 2H), 3.2 (s,3H), 2.43 (s, 3H). Separation by chiral HPLC provides enantiomersII-111a-b.

Example 322 Preparation of Compound Nos. II-112 and II-112a-d

2,6-Dimethyl-1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline (300 mg, 1.08mmol) was dissolved in DMF (4 mL). Sodium hydride (172 mg, 4.32 mmol)was added and the mixture was stirred at RT for 30 min.3-(2-Methyl-oxiranyl)-pyridine (733 mg, 5.43 mmol) in 1 mL DMF was addeddropwise into the reaction mixture, which was stirred for 5 h at RT. Thereaction was monitored by TLC and LCMS. After consumption of startingmaterial, the reaction was quenched with ice and extracted with EtOAc(2×100 mL). The organic layer was washed with water (2×100 mL), driedover anhydrous sodium sulfate and concentrated to obtain the crude thatwas purified by column chromatography (silica gel 100-200 mesh, Eluent:6% MeOH in DCM) to obtain 120 mg of1-(2,6-dimethyl-1-phenyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-2-pyridin-3-yl-propan-2-ol(racemate) and followed by chiral separation. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 8.25 (s, 1H), 8.2 (d, 1H), 7.6 (d, 1H), 7.4 (m, 3H), 7.2 (s, 1H),7.19 (m, 3H), 6.65 (d, 1H), 6.4 (d, 1H), 5.5 (s, 1H), 4.0 (d, 1H), 3.43(d, 1H), 3.2 (m, 1H), 3.0 (m, 3H), 2.6 (s, 3H), 2.3 (s, 3H), 1.6 (s,3H). Separation by chiral HPLC provided diastereomers II-112a-b.

Example 323 Preparation of Compound Nos. II-113 and II-113a-d

2,6-Dimethyl-1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline (300 mg, 1.08mmol) was dissolved in DMF (3 mL). Sodium hydride (172 mg, 4.32 mmol)was added and the mixture stirred at RT for 30 min. 4-Oxiranyl-pyridine(657 mg, 5.43 mmol) in 1 mL DMF was added dropwise into the reactionmixture, which was stirred at RT for 5 h. The reaction was monitored byTLC and LCMS. After consumption of starting material, the reaction wasquenched with ice and extracted with EtOAc (2×100 mL). The organic layerwas washed with water, dried over anhydrous sodium sulfate andconcentrated to obtain the crude product that was purified by columnchromatography (eluent: 10% MeOH in DCM) to obtain 220 mg of2-(2,6-dimethyl-1-phenyl-1,2,3,4-tetrahydro-3-carbolin-9-yl)-1-pyridin-4-yl-ethanol(M6792, racemate) and followed by chiral separation. ¹H NMR (CD₃OD, Freebase) δ (ppm): 8.17 (d, 2H), 7.35 (m, 4H), 7.09 (d, 2H), 7.0 (m, 3H),6.9 (d, 1H), 4.8 (t, 1H), 4.6 (s, 1H), 4.08 (dd, 1H), 3.45 (dd, 1H), 3.0(m, 1H), 2.8 (m, 2H), 2.6 (m, 1H), 2.4 (s, 3H), 2.2 (s, 3H). Separationby chiral HPLC provided diastereomers II-113a-b.

Example 324 Preparation of Compound Nos. II-114 and II-114a-b

1-(6-Bromo-pyridin-3-yl)-2-(3,6-dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-ethanol(2 g, 4.9 mmol) was dissolved in DMF (20 mL), and the mixture was purgedwith nitrogen. Zinc cyanide (1.16 g, 9.9 mmol) and Pd(PPh₃)₄ (339 mg,0.294 mmol) were added, and the mixture heated at 150° C. for 2 h. Thereaction was monitored by LCMS. The reaction mixture was allowed to coolat RT, diluted with EtOAc (250 mL) and filtered. The filtrate was washedwith water (3×100 mL). The organic layer was dried over anhydrous sodiumsulfate and concentrated to obtain the crude that was purified byreverse phase chromatography to obtain 100 mg of5-[2-(3,6-dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile.This was followed by chiral separation. ¹H NMR (CDCl₃, Free base) δ(ppm): 8.62 (s, 1H), 8.03 (s, 1H), 7.73 (d, 1H), 7.6 (d, 1H), 7.5 (s,1H), 5.25 (d, 1H), 4.45 (d, 1H), 4.3 (dd, 1H), 3.55 (dd, 2H), 2.8 (m,1H), 2.7 (m, 2H), 2.5 (s, 3H), 2.45 (s, 3H), 2.4 (m, 1H). Separation bychiral HPLC provided enantiomers II-114a-b.

Example 325 Preparation of Compound Nos. II-115 and II-115a-d

Compound Nos. II-115 and II-115a-d are prepared in an analogous fashionto Compound Nos. 129 and 129a-d (Example 110), using2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole as the startingmaterial.

Example 326 Preparation of Compound Nos. II-116 and II-116a-b

To a degassed solution of aza-allylcyano alcohol (200 mg, 0.53 mmol) and1,3-dimethylbarbituric acid (251 mg, 1.61 mmol) in DCM (5 mL) was addedPd(PPh₃)₄ (24 mg, 0.020 mmol) at RT and the reaction mixture was stirredat RT for 45 min. The progress of reaction was monitored by TLC andLCMS. The reaction mixture was diluted with water and the organic layerwas separated. The aqueous layer was basified with saturated aq NaHCO₃and extracted with DCM. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by reverse phase HPLC to yield title compound. ¹H NMR (CD₃OD,TFA salt) δ (ppm): 8.2 (s, 1H), 8.0 (s, 1H), 7.68 (d, 2H), 7.6 (d, 2H),5.2 (dd, 1H), 4.5 (dd, 1H), 4.45 (s, 2H), 4.33 (dd, 1H), 3.6 (t, 2H),3.25 (d, 1H), 3.1 (d, 1H), 2.5 (s, 3H). Separation by chiral HPLCprovides enantiomers II-116a-b.

Example 327 Preparation of Compound Nos. II-117 and II-117a-b

Compound Nos. II-117 and II-117a-b are prepared in an analogous fashionto Compound Nos. 5 and 5a-b (Example 5), using2-fluoro-5-(2-methyloxiran-2-yl)pyridine as the epoxide.

Example 328 Preparation of Compound Nos. II-118 and II-118a-b

To an ice-cooled stirred solution of8-chloro-2-cyclobutyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g,3.84 mmol) in DMF (10 mL) was added sodium hydride (60%, 462 mg, 11.55mmol). After stirring for 10 min, 3-(2-methyloxiran-2-yl)pyridine (780mg, 5.77 mmol) was added into the reaction mixture, which was stirred atRT for 16 h. The progress of reaction was monitored by TLC and LCMS. Thereaction mixture was quenched with ice-water and extracted with EtOAc(2×100 mL). The organic layer was washed with water (5×100 mL), driedover anhydrous sodium sulfate and concentrated under reduced pressure.The product was crystallized from ether:hexane (50:50) to yield thetitle compound (1.0 g). The product was further purified by chiral HPLCto give enantiomers II-118a and II-118b. ¹H NMR (CD₃OD, Di-HCl salt) δ(ppm): 8.7 (m, 3H), 7.79 (d, 1H), 7.43 (d, 1H), 6.9 (m, 2H), 4.7 (d,1H), 4.4 (dd, 2H), 4.15 (t, 1H), 3.95 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H),3.5 (m, 1H), 2.4 (m, 4H), 1.9 (m, 3H), 1.8 (d, 3H).

Example 329 Preparation of Compound No. II-119

To a stirred solution of3,6-dimethyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (201mg, 1.0 mmol) in NMP (3 mL) was added powdered KOH (392 mg, 7.0 mmol).After stirring for 10 min at RT, 2-(trifluoromethyl)-5-vinylpyridine(346 mg, 2.0 mmol) was added to the reaction mixture and stirringcontinued for another 3 h. The progress of reaction was monitored by TLCand NMR. The reaction mixture was diluted with water (20 mL) andextracted with EtOAc (3×20 mL). The organic layer was washed with water(5×20 mL), dried over anhydrous sodium sulfate and concentrated underreduced pressure to afford crude material, which was purified by reversephase HPLC to yield3,6-dimethyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine(80 mg). ¹H NMR (CDCl₃, TFA salt) δ (ppm): 8.38 (s, 1H), 8.0 (s, 1H),7.5 (d, 2H), 7.4 (d, 1H), 4.4 (t, 2H), 3.58 (s, 2H), 3.2 (t, 2H), 2.68(t, 2H), 2.5 (t, 2H), 2.47 (s, 3H), 2.38 (s, 3H).

Example 330 Preparation of Compound Nos. II-120 and II-120a-d

9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorine(250 mg, 1.10 mmol) was dissolved in DMF (3 mL), sodium hydride (221 mg,5.53 mmol) was added and the mixture stirred at RT for 5 min.2-(4-Fluoro-phenyl)-oxirane (305 mg, 2.21 mmol) in 2 mL DMF was addeddropwise into the reaction mixture and was stirred at RT for 16 h. Thereaction was monitored by TLC and LCMS. After completion of reaction,the mixture was quenched with ice cold water (100 mL) and extracted withEtOAc (100 mL). The organic layer was washed with water (5×50 mL), driedover sodium sulfate and concentrated to obtain the crude product thatwas purified by reverse phase HPLC followed by chiral HPLC to obtain 190mg of1-(4-fluoro-phenyl)-2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-ethanol.¹H NMR (CD₃OD, HCl salt) δ (ppm): 7.32 (d, 1H), 7.3 (s, 1H), 7.1 (t,2H), 7.0 (m, 3H), 5.08 (t, 1H), 4.4 (dd, 1H), 4.19 (dd, 1H), 3.6 (m,2H), 3.45 (m, 1H), 3.0 (d, 1H), 2.6 (m, 2H), 2.4 (s, 3H), 2.2 (m, 2H),2.0 (m, 1H). Separation by chiral HPLC provided diastereomers II-120a-b.

Example 331 Preparation of Compound Nos. II-121 and II-121a-d

9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene(150 mg, 0.66 mmol) was dissolved in DMF (2 mL), sodium hydride (79 mg,1.98 mmol) was added and the mixture was stirred at RT for 5 min.2-(4-Fluoro-phenyl)-2-methyl-oxirane (201 mg, 1.32 mmol) was addeddropwise into the reaction mixture and stirred at RT for 18 h. Thereaction was monitored by TLC and LCMS. After consumption of startingmaterial, the reaction mixture was quenched with ice cold water (100 mL)and extracted with EtOAc (2×100 mL). The combined organic layer waswashed with water (2×100 mL), dried over anhydrous sodium sulfate andconcentrated to obtain the crude product, which was purified by columnchromatography (neutral alumina) Eluent:—2% MeOH in DCM followed bychiral HPLC to obtain 77 mg of2-(4-fluoro-phenyl)-1-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-propan-2-ol.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.4 (m, 2H), 7.2 (m, 2H), 7.0 (m, 3H),5.08 (t, 1H), 4.3 (d, 1H), 4.15 (d, 1H), 3.65 (m, 1H), 3.5 (m, 2H), 3.3(m, 1H), 2.90 (m, 2H), 2.7 (m, 1H), 2.4 (s, 3H), 2.2 (m, 3H), 1.62 (s,3H). Separation by chiral HPLC provided diastereomers II-121a-b.

Example 332 Preparation of Compound Nos. II-122 and II-122a-d

To a solution of11-aza-10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (200mg, 0.88 mmol) in DMF (5 mL), NaH (105 mg, 2.6 mmol, 60% dispersion inmineral oil) was added at 0° C. and the reaction mixture was stirred for10 min. 4-oxiranyl-pyridine (213 mg, 1.76 mmol) was added and thereaction mixture was stirred at RT overnight. The reaction was monitoredwith LCMS. The reaction mixture was quenched with MeOH (2 mL),concentrated under reduced pressure to obtain the product that waspurified by reverse phase column chromatography to obtain the 39 mg ofproduct as the free base. ¹H NMR (CD₃OD, freebase) δ (ppm): 8.4 (d, 2H),7.63 (d, 1H), 7.29 (dd, 2H), 6.95 (t, 1H), 5.0 (t, 1H), 4.3 (m, 3H),3.21 (m, 1H), 2.9 (m, 4H), 2.7 (m, 1H), 2.57 (s, 3H), 2.52 (m, 1H), 1.9(m, 3H). Separation by chiral HPLC provides diastereomers II-122a-b.

Example 333 Preparation of Compound Nos. II-123 and II-123a-b

A mixture of9-chloro-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and7-chloro-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.00 g,8.5 mmol) was dissolved in DMF (15 mL). Sodium hydride (1.708 g, 42.71mmol) was added at 0-10° C. and stirred at the same temperature for 15min., 3-(2-methyloxiran-2-yl)pyridine (2.309 g, 17.08 mmol) was addeddropwise into the reaction mixture and the mixture was stirred at RT for16 h. The reaction was monitored by TLC and LCMS. After consumption ofstarting material, the reaction mixture was quenched with ice cold water(100 mL) and extract with EtOAc (300 mL). The organic layer was washedwith water (5×100 mL). The organic layer dried over anhydrous sodiumsulfate and concentrated under reduced pressure to obtain the crude. Thecrude product was purified by reverse phase column chromatography toobtain 350 mg of1-(7-chloro-2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol.¹H NMR (CD₃OD, HCl salt) δ (ppm): 8.68 (m, 3H), 7.95 (m, 1H), 7.29 (d,1H), 6.9 (m, 1H), 4.68 (dd, 1H), 4.38 (m, 2H), 4.32 (dd, 1H), 3.9 (m,1H), 3.52 (m, 2H), 3.25 (m, 1H), 3.12 (s, 3H), 2.35 (d, 3H), 1.83 (d,3H). Separation by chiral HPLC provided enantiomers II-123a-b.

Example 334 Preparation of Compound Nos. II-124 and II-124a-b

A mixture of9-chloro-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and7-chloro-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.00 g,8.5 mmol) was dissolved in DMF (15 mL). Sodium hydride (1.708 g, 42.71mmol) was added at 0-10° C. and stirred at the same temperature for 15min., 3-(2-methyloxiran-2-yl)pyridine (2.309 g, 17.08 mmol) was addeddropwise into the reaction mixture and the mixture was stirred at RT for16 h. The reaction was monitored by TLC and LCMS. After consumption ofstarting material, the reaction mixture was quenched with ice cold water(100 mL) and extract with EtOAc (300 mL). The organic layer was washedwith water (5×100 mL). The organic layer dried over anhydrous sodiumsulfate and concentrated under reduced pressure to obtain the crude. Thecrude product was purified by reverse phase column chromatography toobtain 35 mg of1-(9-chloro-2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol.¹H NMR (CD₃OD, freebase) δ (ppm): 8.46 (s, 1H), 8.34 (d, 1H), 7.82 (d,1H), 7.29 (t, 1H), 6.87 (d, 1H), 6.77 (d, 1H), 4.22 (dd, 2H), 3.99 (q,2H), 2.73 (m, 4H), 2.5 (s, 3H), 2.3 (s, 3H), 1.66 (s, 3H). Separation bychiral HPLC provided enantiomers II-124a-b.

Example 335 Preparation of Compound Nos. II-125 and II-125a-d

8,10-Dimethyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (700mg, 2.92 mmol) in DMF (20 mL) was stirred at 0° C. for 5 min. NaH (580mg, 14.60 mmol) was added slowly at 0° C. After 10 min. stirring,4-(oxiran-2-yl)pyridine (710 mg, 5.87 mmol) was added and the reactionmixture was stirred at RT for 15 h. The reaction mixture was poured inice-cold water (150 mL) and extracted with EtOAc (3×200 mL). Thecombined organic layer was washed with water (6×300 mL), dried overanhydrous sodium sulfate and concentrated to obtain semi-solid residuethat was washed with hexane (3×20 mL). The residue was suspended inether (30 mL) stirred for 1 h. The suspension was filtered to give 200mg of2-(8,10-dimethyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethanol.¹H NMR (CD₃OD, HCl salt) δ (ppm): 8.79 (d, 2H), 8.03 (d, 2H), 7.13 (s,1H), 6.82 (s, 1H), 5.22 (dd, 1H), 5.01 (t, 1H), 4.67 (dd, 1H), 4.48 (dd,1H), 4.79 (m, 1H), 3.64 (t, 2H), 3.4 (m, 3H), 2.9 (m, 1H), 2.73 (s, 3H),2.37 (s, 3H), 2.22 (m, 3H). Separation by chiral HPLC provideddiastereomers II-125a-b.

Example 336 Preparation of Compound Nos. II-126 and II-126a-b

9-Aza-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (160 mg, 0.88mmol) was dissolved in DMF (8 mL). Sodium hydride (63 mg, 2.64 mmol) wasadded at 0-10° C. and stirred at the same temperature for 15 min.,3-(2-methyloxiran-2-yl)pyridine (480 mg, 3.55 mmol) in DMF (2 mL) wasadded dropwise into the reaction mixture and the mixture was stirred atRT for 16 h. The reaction was monitored by LCMS. After consumption ofstarting material, the reaction mixture was quenched with ice cold water(4 mL) and solvent was evaporated to obtain the crude product, which waspurified by reverse phase column chromatography to obtain 15 mg ofproduct. ¹H NMR (CD₃OD, freebase) δ (ppm): 8.51 (s, 1H), 8.3 (d, 1H),8.13 (d, 1H), 7.83 (d, 1H), 7.57 (d, 1H), 7.31 (t, 1H), 6.99 (t, 1H),4.33 (dd, 2H), 3.78 (dd, 2H), 3.0 (m, 1H), 2.85 (m, 1H), 2.75 (m, 2H),2.53 (s, 3H), 1.69 (s, 3H). Separation by chiral HPLC providesenantiomers II-126a-b.

Example 337 Preparation of Compound Nos. II-127 and II-127a-d

9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene(150 mg, 0.66 mmol) was dissolved in DMF (1 mL), sodium hydride (47 mg,1.98 mmol) was added and the mixture was stirred at RT for 5 min.3-(2-Methyl-oxiranyl)-pyridine (143 mg, 1.06 mmol) was added dropwiseinto the reaction mixture and stirred at RT for 2 h. The reaction wasmonitored by TLC and LCMS. After consumption of starting material, thereaction mixture was quenched with ice cold water (20 mL) and extractedwith EtOAc (2×100 mL). The combined organic layer was washed with water(2×100 mL), dried over anhydrous sodium sulfate and concentrated toobtain the crude product, which was purified by column chromatography(silica gel 100-200 mesh, Eluent:—15% MeOH in DCM) to obtain 80 mg of1-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-2-pyridin-3-yl-propan-2-ol.¹H NMR (CD₃OD, HCl salt) δ (ppm): 8.66 (dd, 2H), 8.56 (s, 1H), 7.92 (t,1H), 7.20 (s, 1H), 6.77 (t, 2H), 5.04 (t, 1H), 3.75 (dd, 2H), 3.72 (m,2H), 3.6 (m, 1H), 3.44 (m, 2H), 3.22 (d, 1H), 2.75 (m, 1H), 2.73 (s,3H), 2.16 (m, 3H), 1.8 (s, 3H). Separation by chiral HPLC providedenantiomers II-127a-b.

Example 338 Preparation of Compound Nos. II-128 and II-128a-d

9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene(200 mg, 0.88 mmol) was dissolved in DMF (3 mL), sodium hydride (106 mg,2.65 mmol) was added and stirred for 15 min. at RT.2-Methyl-5-(2-methyl-oxiranyl)-pyridine (263 mg, 1.76 mmol) was addeddropwise into the reaction mixture and the mixture was stirred at RT for3 h. The reaction was monitored by TLC and LCMS. After consumption ofstarting material, the reaction mixture was quenched with ice cold water(20 mL) and extracted with EtOAc (3×30 mL). The combined organic layerwas washed with water (2×60 mL), dried over anhydrous sodium sulfate andconcentrated to obtain the crude product, which was purified by reversephase chromatography to obtain 200 mg of1-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-2-(6-methyl-pyridin-3-yl)-propan-2-ol.¹H NMR (CD₃OD, HCl salt) δ (ppm): 8.5 (d, 1H), 8.3 (s, 1H), 7.79 (d,1H), 7.22 (s, 1H), 6.82 (s, 2H), 5.03 (t, 1H), 4.38 (dd, 2H), 3.8 (m,1H), 3.66 (m, 2H), 3.46 (m, 2H), 3.2 (m, 2H), 2.7 (m, 1H), 2.67 (s, 3H),2.36 (s, 3H), 2.22 (m, 2H), 1.77 (s, 3H). Separation by chiral HPLCprovided enantiomers II-128a-b.

Example 339 Preparation of Compound Nos. II-129 and II-129a-b

7-Aza-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (160 mg, 0.88mmol) was dissolved in DMF (8 mL). Sodium hydride (63 mg, 2.64 mmol) wasadded at 0-10° C. and stirred at the same temperature for 15 min.,3-(2-methyloxiran-2-yl)pyridine (480 mg, 3.55 mmol) in DMF (2 mL) wasadded dropwise into the reaction mixture and the mixture was stirred atRT for 16 h. The reaction was monitored by LCMS. After consumption ofstarting material, the reaction mixture was quenched with ice cold water(4 mL) and solvent was evaporated to obtain the crude product, which waspurified by reverse phase column chromatography to obtain 3 mg ofproduct as the free base. ¹H NMR (CD₃OD, freebase) δ (ppm): 8.46 (s,1H), 8.39 (s, 1H), 8.36 (d, 1H), 7.96 (d, 1H), 7.82 (d, 1H), 7.37 (d,1H), 7.31 (t, 1H), 4.4 (dd, 2H), 3.71 (dd, 2H), 3.0 (m, 1H), 2.9 (m,1H), 2.72 (m, 1H), 2.62 (m, 1H), 2.52 (s, 3H), 1.72 (s, 3H). Separationby chiral HPLC provides enantiomers II-129a-b.

Example 340 Preparation of Compound Nos. II-130 and II-130a-d

To a stirred solution of10-chloro-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole (1.0 g,4.06 mmol) in DMF (50 mL) was added sodium hydride (60%, 406 mg, 10.15mmol). After stirring for 10 min., 3-(2-methyloxiran-2-yl)pyridine (823mg, 6.09 mmol) was added to the reaction mixture, which was stirred atRT for 16 h. The progress of reaction was monitored by TLC and LCMS. Thereaction mixture was quenched with ice-water and extracted with EtOAc(2×100 mL). The organic layer was washed with water (5×100 mL), driedover anhydrous sodium sulfate and concentrated under reduced pressure toobtain the residue that was crystallized with ethanol-hexane to yieldthe 1.2 g of1-(10-chloro-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-2-(pyridin-3-yl)propan-2-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.70 (s, 1H), 8.49 (d, 1H), 7.62 (d,1H), 7.36 (s, 1H), 7.12 (m, 2H), 7.02 (d, 1H), 4.17 (q, 2H), 3.86 (t,1H), 3.19 (m, 1H), 2.86 (m, 1H), 2.74 (m, 3H), 2.41 (m, 2H), 1.85 (m,3H), 1.7 (s, 3H). Separation by chiral HPLC provides diastereomersII-130a-d.

Example 341 Preparation of Compound Nos. II-131 and II-131a-d

9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene(200 mg, 0.88 mmol) was dissolved in DMF (3 ml), sodium hydride (106 mg,2.65 mmol) was added and the mixture was stirred at RT for 15 min.3-Oxiranyl-pyridine (214 mg, 1.76 mmol) was added dropwise into thereaction mixture and the mixture was stirred at RT for 3 h. The reactionwas monitored by TLC and LCMS. After consumption of starting material,the reaction mixture was quenched with ice cold water (20 mL) andextracted with EtOAc (3×30 mL). The combined organic layer was washedwith water (2×60 mL), dried over anhydrous sodium sulfate andconcentrated to obtain the crude product, which was purified by reversephase chromatography to obtain 60 mg of2-(9-Methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyridin-3-yl-ethanolas the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.7 (d, 1H), 8.53 (s,1H), 8.4 (d, 1H), 7.85 (t, 1H), 7.25 (s, 1H), 7.08 (t, 1H), 6.9 (d, 1H),5.28 (t, 1H), 5.03 (t, 1H), 4.42 (s, 2H), 3.76 (m, 1H), 3.6 (m, 2H), 3.4(m, 1H), 3.2 (m, 2H), 2.7 (m, 1H), 2.38 (s, 3H), 2.2 (m, 3H). Separationby chiral HPLC provides diastereomers II-131a-d.

Example 342 Preparation of Compound Nos. II-132 and II-132a-d

1-(2-Methoxy-pyridin-4-yl)-2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-ethanol(45 mg, 0.119 mmol) and 47% aqueous HBr (4 mL) and heated at 100° C. for45 min. The reaction was monitored by TLC and LCMS. After consumption ofstarting material, the reaction mixture was cooled to RT and basifiedwith ammonia and extracted with EtOAc (2×25 mL). The organic layer wasdried over anhydrous sodium sulfate and concentrated and the crudeproduct was purified by reverse phase chromatography to obtain 20 mg of4-(2-(2,3,5,6-tetrahydro-10-methyl-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-hydroxyethyl)pyridin-2(1H)-one.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.43 (d, 1H), 7.23 (m, 2H), 7.05 (t,1H), 6.7 (m, 1H), 6.5 (d, 1H), 4.79 (m, 1H), 4.3 (m, 2H), 3.9 (m, 2H),3.8 (m, 1H), 3.6 (m, 1H), 3.4 (m, 2H), 3.1 (m, 1H), 2.6 (m, 1H), 2.4 (s,3H), 2.3 (m, 2H), 1.9 (m, 1H). Separation by chiral HPLC providedenantiomers II-132a-b.

Example 343 Preparation of Compound No. II-133

To a stirred solution of6,8,8-trimethyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine(75 mg, 0.348 mmol) in DMF (1.5 mL) was added sodium hydride (42 mg,1.0465 mmol). After stirring for 10 min at RT, a solution of2-(6-methylpyridin-3-yl)ethyl trifluoromethanesulfonate (304 mg, 1.046mmol) in DMF (1.5 mL) was added to the reaction mixture and stirringcontinued at RT for 16 h. The progress of reaction was monitored by TLCand LCMS. The reaction mixture was diluted with water and extracted withEtOAc (3×25 mL). The organic layer was washed with water (3×25 mL),dried over anhydrous sodium sulfate and concentrated to afford crudemass, which was purified by reverse phase HPLC. ¹H NMR (CDCl₃, TFA salt)δ (ppm): 8.42 (s, 1H), 8.31 (d, 1H), 7.7 (d, 1H), 7.57 (d, 1H), 7.1 (d,1H), 7.0 (t, 1H), 4.5 (t, 2H), 3.63 (s, 2H), 3.2 (t, 2H), 2.57 (s, 8H),1.42 (s, 6H).

Example 344 Preparation of Compound Nos. II-134 and II-134a-b

To a solution of 1,2,3,4,5,6-hexahydro-3,9-dimethylazepino[4,5-b]indole(3 g, 14.01 mmol) in DMF (40 mL), NaH (2.8 g, 70 mmol, 60% dispersion inmineral oil) was added slowly at 0° C. The solution was stirred at 0° C.for 10 min. 4-(2-Methyloxiran-2-yl)pyridine (3.8 g, 2.8 mmol) was addedand the reaction mixture was stirred at RT for 15 h. The reactionmixture was poured into ice-cold water (300 mL) and extracted with EtOAc(2×200 mL). The organic layer was washed with water (5×200 mL), driedover anhydrous sodium sulfate and concentrated under reduced pressuregave an oily residue that was purified by column chromatography usingsilica gel (100-200 mesh) and 10 MeOH-DCM as eluting system followed bychiral preparative HPLC to afford the 300 mg of pure product. ¹H NMR(CDCl₃, freebase) δ (ppm): 8.59 (d, 2H), 7.38 (d, 2H), 7.25 (s, 1H),7.18 (d, 1H), 6.96 (d, 1H), 4.23 (dd, 2H), 2.89 (m, 2H), 2.75 (m, 4H),2.6 (m, 2H), 2.43 (s, 3H), 2.42 (s, 3H), 1.58 (s, 3H). Separation bychiral HPLC provided enantiomers II-134a-b.

Example 345 Preparation of Compound Nos. II-135 and II-135a-b

3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1 g, 4.6 mmol)in DMF (10 mL) was stirred at RT for 5 min. NaH (60%, 933 mg, 23.33mmol) was added and the reaction mixture was stirred at RT for 10 min.3-(2-methyloxiran-2-yl)pyridine (1.26 g, 9.34 mmol) was added to thereaction mixture and the mixture was stirred at RT for 16 h. Thereaction mixture was poured into ice-water and extracted with EtOAc (200mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum to obtain the crude product, which waspurified by column chromatography using silica gel: 100-200 mesh and 10%MeOH/DCM/1 mL NH4OH to obtain 600 mg of1-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(pyridin-3-yl)propan-2-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.74 (s, 1H), 8.54 (d, 1H), 7.71 (d,1H), 7.26 (s, 1H), 7.27 (m, 1H), 7.19 (d, 1H), 6.96 (d, 1H), 4.26 (dd,2H), 2.91 (m, 2H), 2.9 (m, 4H), 2.74 (m, 2H), 2.44 (s, 6H), 1.63 (s,3H). Separation by chiral HPLC provided enantiomers II-135a-b.

Example 346 Preparation of Compound Nos. II-136 and II-136a-b

A mixture of5-(1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxypropan-2-yl)picolinonitrile(300 mg, 0.833 mmol), crushed KOH (140 mg, 2.499 mmol) in 12 mLtert-butanol was heated at 80° C. for 2 h. The reaction was monitored byTLC. The reaction mixture was allowed to cool at RT, diluted with brine(30 mL) and extracted with ethyl acetate (2×100 mL). The combinedorganic layer was washed with water (3×100 mL), dried over anhydroussodium sulfate and concentrated to obtain the crude product, which waspurified by Preparative HPLC followed by chiral HPLC to obtain5-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridine-2-carboxamide.¹H NMR (CDCl₃, freebase) δ (ppm): 8.49 (s, 1H), 8.04 (d, 1H), 7.86 (d,1H), 7.66 (s, 1H), 7.01 (s, 1H), 6.85 (s, 1H), 6.78 bs (NH), 5.48 s(OH),4.16 (dd, 2H), 3.44 (q, 2H), 2.9 (m, 2H), 2.7 (m, 2H), 2.45 (s,3H), 2.35 (s, 3H), 2.35 (s, 3H), 1.6 (s, 3H). Separation by chiral HPLCprovided enantiomers II-136a-b.

Example 347 Preparation of Compound Nos. II-137 and II-137a-b

These compounds were synthesized in an analogous fashion to CompoundNos. 55 and 55a-b, using3,6-dimethyl-6,7,8,9-tetrahydro-5H-1,2,6,9-tetraaza-fluorene as thecarboline portion. Separation by chiral HPLC provides enantiomersII-137a-b.

Example 348 Preparation of Compound Nos. II-138 and II-138a-d

A solution of benzyl protected fused carboline compound (70 mg, 0.16mmol) in HPLC grade MeOH (70 mL) was subjected to hydrogenation inH-Cube. The solvent was removed under reduced pressure to afford an oilyresidue that was purified by preparative HPLC to give 3 mg of desiredcompound. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.67 (s, 2H), 7.28 (m, 3H),7.04 (d, 1H), 5.21 (m, 1H), 5.04 (t, 1H), 4.39 (m, 2H), 3.67 (m, 3H),3.25 (m, 2H), 3.03 (m, 1H), 2.68 (m, 1H), 2.41 (s, 3H), 2.19 (m, 3H).Separation by chiral HPLC provides diastereomers II-138a-d.

Example 349 Preparation of Compound Nos. II-139 and II-139a-d

A suspension of2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(1cH)-yl)-1-(1-trityl-1H-imidazol-2-yl)ethanol (0.4 g, 0.69 mmol) in MeOH(10 mL), 1N HCl (1 mL) was added and the reaction mixture was stirred atRT for 2 h. The reaction mixture concentrated under vacuum to obtain thecrude product that was basified with satd. sodium bicarbonate solutionand extracted with EtOAc (50 mL). The organic layer was dried overanhydrous sodium sulfate, and concentrated under vacuum to obtain thecrude product, which was purified by reverse HPLC to obtain 11.30 mg1-(1H-imidazol-2-yl)-2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)ethanol.¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.44 (s, 2H), 7.27 (s, 1H), 7.13 (d,1H), 6.99 (d, 1H), 5.37 (t, 1H), 5.1 (m, 1H), 4.56 (dd, 1H), 4.46 (dd,1H), 3.67 (m, 3H), 3.42 (m, 1H), 3.24 (m, 2H), 2.7 (m, 1H), 2.4 (s, 3H),2.2 (m, 3H).

Example 350 Preparation of Compound Nos. II-140 and II-140a-d

To a stirred solution of compound2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(1-trityl-1H-imidazol-5-yl)ethanol(400 mg, 0.69 mmol) in MeOH (10 mL), 1N HCl (1 mL) at 0° C. was added.The reaction mixture was stirred at RT for 2 h. The reaction mixtureconcentrated under vacuum to obtain the crude product that was basifiedwith sat sodium bicarbonate solution and extracted with EtOAc (50 mL).The organic layer dried on anhydrous sodium sulfate, and concentratedunder vacuum to obtain the crude product that was purified by reversephase HPLC to obtain1-(1H-imidazol-5-yl)-2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)ethanol(12 mg) as the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.79 (s, 1H),7.4 (s, 1H), 7.27 (s, 1H), 7.2 (dd, 1H), 7.01 (d, 1H), 5.18 (t, 1H),5.04 (m, 1H), 4.39 (m, 2H), 3.67 (m, 3H), 3.42 (m, 2H), 3.2 (m, 1H), 2.7(m, 1H), 2.4 (s, 3H), 2.2 (m, 3H). Separation by chiral HPLC providesdiastereomers II-140a-d.

Example 351 Preparation of Compound Nos. II-141 and II-141-a-b

To a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(90 mg, 0.466 mmol) in DMF (2 mL), sodium hydride (60%, 33 mg, 1.44mmol) was added. After stirring for 10 min., methyl5-(2-methyloxiran-2-yl)nicotinate (1.09 g, 12.4 mmol) was added to thereaction mixture, which was stirred at RT for 16 h. The progress ofreaction was monitored by TLC and LCMS. The reaction mixture wasquenched with ice-water and extracted with EtOAc (2×100 mL). The aqueouslayer was lyophilized and purified by reverse phase HPLC purification toobtain the 10 mg of5-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridine-3-carboxylicacid. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.9 (d, 1H), 8.7 (d, 1H), 8.57(d, 1H), 7.11 (s, 1H), 6.74 (d, 2H), 4.67 (dd, 1H), 4.33 (m, 2H), 4.29(dd, 1H), 3.9 (t, 1H), 3.6 (m, 2H), 3.2 (m, 1H), 3.11 (s, 3H), 2.3 (s,3H), 1.79 (d, 3H). Separation by chiral HPLC provides enantiomersII-141a-b.

Example 352 Preparation of Compound Nos. II-142 and II-142a-b

2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40 mg, 0.200mmol) was dissolved in 1 ml DMF. Sodium hydride (24 mg, 0.600 mmol) wasadded at 0° C. and the reaction mixture was stirred at RT for 10 min.5-(2-methyloxiran-2-yl)oxazole (35 mg, 0.280 mmol) in DMF (1 mL) wasadded dropwise over 10 min. and the reaction mixture was stirred at RTfor 12 h. The reaction was monitored by TLC and LCMS. Ice cold water wasadded to the reaction mixture and then extracted with EtOAc (3×20 mL).The combined organic layer was washed with water (4×10 mL), dried overanhydrous sodium sulfate and concentrated to obtain the crude product,which was purified by reverse phase chromatography to obtain the 20 mgof1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(oxazol-5-yl)propan-2-olas the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.09 (s, 1H), 7.18(s, 1H), 6.97 (d, 1H), 6.92 (d, 1H), 6.8 (s, 1H), 4.7 (m, 1H), 4.35 (m,3H), 3.9 (m, 1H), 3.56 (m, 1H), 3.25 (m, 2H), 3.09 (s, 3H), 2.37 (s,3H), 1.58 (s, 3H). Separation by chiral HPLC provides enantiomersII-142a-b.

Example 353 Preparation of Compound Nos. II-143 and II-143a-b

2-(2-Chloropyridin-3-yl)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol(100 mg, 0.277 mmol) and crushed potassium hydroxide (106 mg, 1.89 mmol)in 3 mL tert. butanol were heated at 90° C. for 4 h. The reactionmixture was monitored by TLC and LCMS. The reaction mixture was cooledat RT, diluted with 100 mL brine solution and extracted with EtOAc(3×100 mL). The combined organic layer was washed with brine (3×100 mL),dried over anhydrous sodium sulfate and concentrated to obtain the crudeproduct, which was purified by reverse phase chromatography to get the35 mg of3-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridin-2(1H)-oneas the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 7.79 (d, 1H), 7.35(m, 2H), 7.17 (s, 1H), 6.93 (d, 1H), 6.34 (t, 1H), 4.61 (d, 2H), 4.3 (d,2H), 3.9 (m, 1H), 3.8 (m, 1H), 3.36 (m, 2H), 3.1 (s, 3H), 2.37 (s, 3H),1.51 (s, 3H). Separation by chiral HPLC provides enantiomers II-143a-b.

Example 354 Preparation of Compound No. II-144

To a solution of6-methyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (200 mg,1.068 mmol) in DMF (1 mL) was added a suspension of NaH (128.0 mg, 3.24mmol) in DMF (1 mL). After stirring for 5 min. at RT, a solution of2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (932 mg, 3.204mmol) in DMF (1 mL) was added dropwise into the reaction mixture andstirring continued for another 3 h. The progress of reaction wasmonitored by TLC and NMR. The reaction mixture was diluted with water(20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washedwith water (3×20 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude material, which waspurified by silica gel flash chromatography eluting with 10% MeOH-DCM toyield6-methyl-9-(2-(6-methylpyridin-3-yl)ethyl)-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine(90 mg) as a free base. The free base was converted into tri-HCl salt bytreatment with ethanolic HCl. ¹H NMR (CD₃OD, Tri-HCl salt) δ (ppm): 8.76(s, 1H), 8.40 (m, 3H), 7.80 (d, 1H), 7.50 (t, 1H), 4.90-4.70 (m, 3H),4.42 (m, 1H), 3.95 (m, 1H), 3.66 (m, 1H), 3.42-3.30 (m, 4H), 3.15 (s,3H), 2.76 (s, 3H).

Example 355 Preparation of Compound Nos. II-145 and II-145a-b

2,8,9-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (400 mg, 1.86mmol) 4 mL DMF, cooled to 0° C. and sodium hydride (224 mg, 5.60 mmol)was added portionwise at the same temperature.3-(2-methyloxiran-2-yl)pyridine (504 mg, 3.73 mmol) in DMF (1 mL) wasadded to the reaction mixture and allowed to stir at RT for 12 h. Aftercomplete consumption of starting material, the reaction mixture waspoured in to ice water and extracted with EtOAc (3×100 mL). The combinedorganic layer was washed with water (3×50 mL), dried over anhydroussodium sulfate and concentrated to obtain the crude product, which wascrystallized with ether and hexane to obtain 400 mg of2-(pyridin-3-yl)-1-(2,8,9-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol.¹H NMR (DMSO, freebase) δ (ppm): 8.59 (s, 1H), 8.42 (d, 1H), 7.73 (d,1H), 7.31 (t, 1H), 7.1 (d, 1H), 6.73 (d, 1H), 4.11 (dd, 2H), 3.74 (s,2H), 3.4 (m, 2H), 2.6 (m, 2H), 2.37 (s, 6H), 2.22 (s, 3H), 1.5 (s, 3H).Separation by chiral HPLC provides enantiomers II-145a-b.

Example 356 Preparation of Compound Nos. II-146 and II-146a-d

2,3,8-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (214 mg, 1mmol) was dissolved in DMF (3 mL) and NaH (80 mg, 3.33 mmol) was addedportionwise at 0° C. The reaction mixture was stirred at 0° C. for 15min. The solution of 3-(2-methyloxiran-2-yl)pyridine (270 mg, 2 mmol) inDMF (2 mL) was added dropwise at 0° C. and the reaction mixture wasstirred at 0° C. for 10 min and at RT for 16 h. Completion of reactionwas monitored by LCMS. The reaction mixture was poured onto crushed iceslowly and extracted with EtOAc (3×30 mL). The organic layer was washedwith water (7×40 mL), dried over anhydrous sodium sulfate andconcentrated under vacuum to obtain the crude product that was purifiedby reverse HPLC to give 23 mg of2-(pyridin-3-yl)-1-(2,3,8-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.73 (s, 1H), 8.47 (d, 1H), 7.2 (d,1H), 7.11 (s, 1H), 7.04 (d, 2H), 6.90 (d, 1H), 4.15 (dd, 2H), 3.78 (dd,1H), 3.6 (dd, 1H), 2.9 (m, 2H), 2.7 (dd, 1H), 2.43 (s, 3H), 2.4 (s, 3H),1.6 (s, 3H), 1.14 (d, 3H). Separation by chiral HPLC provideddiastereomers II-146a-d.

Example 357 Preparation of Compound Nos. II-147 and II-147a-d

To a solution of8-chloro-2,3-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg,2.13 mmol) in 4 mL of DMF was added sodium hydride (256 mg, 6.40 mmol)at 0° C., and stirred for 10 min. 3-(2-methyloxiran-2-yl)pyridine (432mg, 3.20 mmol) was added and the mixture was stirred at RT for 12 h. Thereaction was monitored by TLC and LCMS. The reaction mixture was pouredinto ice cold water and extracted with EtOAc (2×50 mL). The combinedorganic layer was washed with water (5×25 mL), dried over anhydroussodium sulfate, concentrated to obtain the crude product, which wascrystallized in n-hexane to obtain 350 mg of1-(8-chloro-2,3-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.72 (s, 1H), 8.47 (d, 1H), 7.52 (d,1H), 7.23 (s, 1H), 6.94 (m, 3H), 4.10 (dd, 2H), 3.65 (m, 1H), 3.40 (m,1H), 2.86 (m, 2H), 2.38 (s, 3H), 2.36 (m, 1H), 1.62 (s, 3H), 1.07 (d,3H). Separation by chiral HPLC provided diastereomers II-147a-b.

Example 358 Preparation of Compound Nos. II-148 and II-148a-b

To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(700 mg, 3.5 mmol) in 3 mL of DMF was added sodium hydride at 0° C. andstirred for 10 min. 4-Chloro-3-(2-methyloxiran-2-yl)pyridine (888 mg,5.25 mmol) in 2 mL of DMF was added and allowed to stir at RT for 12 h.The reaction was monitored by TLC and LCMS. After completion ofreaction, the reaction mixture was poured into ice cold water andextracted with EtOAc (3×50 mL). The combined organic layer was washedwith water (5×50 mL), Dried over anhydrous sodium sulfate, concentratedunder reduced pressure and crystallized in diethyl ether to get thedesired compound (700 mg). ¹H NMR (CDCl₃, freebase) δ (ppm): 9.1 (s,1H), 8.43 (d, 1H), 7.38 (d, 1H), 7.29 (d, 1H), 7.25 (d, 1H), 6.97 (d,1H), 4.7 (d, 1H), 4.23 (d, 1H), 3.63 (m, 2H), 2.8 (m, 2H), 2.75 (m, 2H),2.51 (s, 3H), 2.41 (s, 3H), 1.71 (s, 3H). Separation by chiral HPLCprovided enantiomers II-148a-b.

Example 359 Preparation of Compound Nos. II-149 and II-149a-d

9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene(700 mg, 3.0 mmol) was dissolved in DMF (7 mL) and sodium hydride (360mg, 9.0 mmol) was added portionwise at 0° C. and stirred for 10 min.2-(4-Fluoro-phenyl)-2-methyl-oxirane (720 mg, 4.8 mmol) in 3 mL DMF wasadded dropwise into the reaction mixture and the mixture was stirred atRT for 18 h. The reaction mixture was quenched with ice cooled water andextracted with EtOAc (3×100 mL). The combined organic layer was washedwith water (4×75 mL), dried over anhydrous sodium sulfate andconcentrated to obtain the crude product, which was purified by passingthrough a column of silica gel (100-200 mesh), using the eluent 5% MeOHin DCM to obtain 520 mg of2-(4-fluoro-phenyl)-1-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6,7-triazacyclopenta[c]fluoren-6-yl)-propan-2-ol. ¹H NMR (CDCl₃, freebase) δ(ppm): 8.02 (s, 1H), 7.54 (s, 1H), 7.43 s (OH), 7.37 (t, 2H), 6.93 (t,2H), 4.37 (d, 1H), 4.22 (d, 1H), 4.04 (t, 1H), 3.23 (dd, 1H), 2.9 (m,1H), 2.7 (m, 2H), 2.5 (m, 2H), 2.42 (s, 3H), 2.3 (m, 1H), 1.84 (m, 3H),1.6 (s, 3H). Separation by chiral HPLC provided diastereomers II-149a-d.

Example 360 Preparation of Compound Nos. II-150 and II-150a-d

2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol(350 mg, 1 mmol), formaldehyde (37%, 0.89 g, 10 mmol) and formic acid(922 mg, 20 mmol) was stirred at 100° C. for 12 h. The progress of thereaction was monitored by TLC and LCMS. The reaction mixture was washedwith saturated sodium bicarbonate and extracted with DCM (2×25 mL). Thecombined organic layer was washed with water (5×25 mL) dried overanhydrous sodium sulfate and concentrated under vacuum to obtain thecrude product, which was subjected to preparative HPLC to obtain 25 mgof2-(9-(hydroxymethyl)-2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.56 (d, 2H), 7.29 (d, 2H), 7.12 (d,1H), 6.98 (d, 1H), 4.9 (dd, 1H), 4.79 (q, 2H), 4.13 (m, 2H), 3.78 (d,1H), 3.72 (d, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 2.67 (m, 2H), 2.49 (s, 3H),2.32 (s, 3H). Separation by chiral HPLC provided diastereomersII-150a-d.

Example 361 Preparation of Compound Nos. II-151 and II-151a-d

2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-4-ol (500 mg,2.314 mmol) in DMF (5.0 mL) was cooled to 0° C. NaH (0.462 mg, 11.57mmol) was added portionwise and stirred for 5 min.3-(2-Methyl-oxiranyl)-pyridine (620 mg, 4.629 mmol) was added dropwiseand the reaction mixture was stirred at RT for 4 h. The reaction wasquenched with ice water and extracted with EtOAc (3×50 mL). The combinedorganic layer was washed with water (2×25 mL), dried over anhydroussodium sulfate and concentrated to get 900 mg crude that was purified byreverse phase HPLC to obtain the product. ¹H NMR (CD₃OD, TFA salt) δ(ppm): 8.57 (m, 2H), 8.48 (m, 1H), 7.85 (m, 1H), 7.21 (s, 1H), 6.78 (d,1H), 6.64 (m, 1H), 5.72 (m, 1H), 4.66 (t, 2H), 4.45 (d, 1H), 4.30 (d,1H), 3.78 (m, 2H), 3.16 (s, 3H), 2.31 (s, 3H), 1.87 (s, 3H). Separationby chiral HPLC provided diastereomers II-151a-b.

Example 362 Preparation of Compound Nos. II-152 and II-152a-d

1,2,8-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.3mmol) in DMF (2.5 mL) was stirred at 0° C. for 5 min. NaH (279 mg, 6.97mmol) was added slowly at 0° C. After min. stirring,3-(2-methyloxiran-2-yl)pyridine (630 mg, 4.6 mmol) in DMF (2.5 mL) wasadded and the reaction mixture was stirred at RT for 18 h. The reactionmixture was poured in ice-cold water (50 mL) and extracted with EtOAc(2×50 mL). The combined organic layer was washed with water (6×50 mL),dried over anhydrous sodium sulfate and concentrated to obtainsemi-solid residue that was washed with hexane (3×20 mL) to obtain 350mg of product that was submitted to chiral reverse phase columnchromatography. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.74 (s, 1H), 8.49 (d,1H), 7.60 (d, 1H), 7.20 (s, 1H), 7.07 (m, 2H), 6.90 (d, 1H), 4.16 (dd,2H), 3.72 (m, 1H), 2.97 (m, 1H), 2.69 (m, 2H), 2.47 (s, 3H), 2.44 (m,1H), 2.42 (s, 3H), 1.66 (s, 3H), 1.42 (d, 3H). Separation by chiral HPLCprovided diastereomers II-152a-d.

Example 363 Preparation of Compound Nos. II-153 and II-153a-b

1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol(1 g, 2.99 mmol) in formaldehyde (37%, 5.69 mL, 59.6 mmol) and formicacid (2.25 mL, 59.6 mmol) was stirred at 100° C. for 24 h. The progressof the reaction was monitored by TLC and LCMS. The reaction mixture wasconcentrated under vacuum to obtain the crude product, which wassubjected to preparative HPLC to obtain pure compound (100 mg). ¹H NMR(CDCl₃, freebase) δ (ppm): 8.7 (s, 1H), 8.5 (d, 1H), 7.8 (d, 1H), 7.23(m, 1H), 7.15 (d, 1H), 6.94 (d, 1H), 4.80 (q, 2H), 4.19 (dd, 2H), 4.17(m, 2H), 3.0 (m, 4H), 2.6 (s, 3H), 2.47 (s, 3H), 1.6 (s, 3H). Separationby chiral HPLC provides enantiomers II-153a-b.

Example 364 Preparation of Compound Nos. II-154 and II-154a-b

1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol(1 g, 2.99 mmol) in formaldehyde (37%, 5.69 mL, 59.6 mmol) and formicacid (2.25 mL, 59.6 mmol) was stirred at 100° C. for 24 h. The progressof the reaction was monitored by TLC and LCMS. The reaction mixture wasconcentrated under vacuum to obtain the crude product, which wassubjected to preparative HPLC to obtain pure compound (100 mg). ¹H NMR(CDCl₃, freebase) δ (ppm): 8.7 (s, 1H), 8.42 (d, 1H), 7.6 (d, 1H), 7.1(s, 1H), 6.9 b (s, 2H), 4.7 (s, 2H), 4.1 (q, 2H), 3.9 (s, 2H), 2.9 (m,3H), 2.8 (m, 1H), 2.6 (s, 3H), 2.39 (s, 3H), 1.6 (s, 3H). Separation bychiral HPLC provides enantiomers II-154a-b.

Example 365 Preparation of Compound No. II-209

2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanone(0.1 g, 0.313 mmol) in 6 mL of DCM was cooled to 0° C., DAST (0.062 mL,0.47 mmol) was added dropwise and the mixture stirred at RT for 2 h. Thereaction was monitored by LCMS. After completion of the reaction, DCM(10 mL) was added, and the reaction was quenched with satd. NaHCO₃solution. The organic layer was separated, dried over anhydrous sodiumsulfate and evaporated to dryness. The crude product was purified bypreparative HPLC to afford 40 mg of the desired compound as the TFAsalt. ¹H NMR (CDCl₃, Free base) δ (ppm): 8.61 (d, 2H), 7.15-7.2 (m, 3H),6.83-6.95 (m, 2H), 4.5 (t, 2H), 3.6 (s, 2H), 2.78-2.63 (m, 2H), 2.6-2.45(m, 5H), 2.4 (s, 3H).

Example 366 Preparation of Compound No. II-210 and II-210a-b

To an ice-cooled stirred solution of1-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido(4,3-b)indol-5-yl)-2-(4-fluorophenyl)-propan-2-ol(500 mg, 1.418 mmol) in DCM (50 mL) was added diethylaminosulfurtrifluoride (DAST) (0.374 mL, 2.85 mmol) and the reaction mixture wasstirred at RT for 1 h. The DCM layer was diluted and washed with aqueoussodium bicarbonate solution. The organic layer was dried over anhydroussodium sulfate and evaporated. The residue was purified by reverse phaseHPLC. ¹H NMR (DMSO, oxalate salt) δ (ppm): 7.45 (m, 2H), 7.30 (d, 1H),7.18 (m, 3H), 6.90 (d, 1H), 4.50 (m, 2H), 4.30 (s, 2H), 3.40 (m, 2H),3.05 (m, 1H), 2.85 (s, 3H), 2.78 (m, 1H), 2.38 (s, 3H), 1.65 (d, 3H).Separation by chiral HPLC provides enantiomers II-210a-b.

Example 367 Preparation of Compound No. II-211 and II-2111a-b

To an ice-cooled stirred solution of1-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(4-fluorophenyl)propan-2-ol(500 mg, 1.3 mmol) in DCM (50 mL) was dropwise added DAST (443 mg, 2.6mmol) and the reaction mixture was stirred at 0° C. for 1 h. Thereaction mixture was diluted with DCM (50 mL), washed with saturatedsodium bicarbonate solution (3×30 mL), dried over anhydrous sodiumsulfate and concentrated. The residue was purified with reverse phaseHPLC to yield8-chloro-5-(2-fluoro-2-(4-fluorophenyl)propyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole.¹H-NMR (DMSO-d6, oxalate salt) δ (ppm): 7.50 (s, 1H), 7.40 (m, 3H), 7.18(t, 2H), 7.05 (d, 1H), 4.60 (m, 2H), 4.25 (m, 2H), 3.05 (m, 2H), 2.85(s, 3H), 2.70 (m, 2H), 1.65 (d, 3H). Separation by chiral HPLC providesenantiomers II-2111a-b.

Example 368 Preparation of Compound Nos. II-212 and II-212a-b

1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol(500 mg, 1.492 mmol) was dissolved in 20 mL DCM, cooled to 0° C. anddiethylaminosulfur trifluoride (720 mg, 4.477 mmol) in DCM (5 mL) wasadded dropwise at the same temperature and stirred for 1 h. The reactionwas monitored by TLC and LCMS. After consumption of starting material,the reaction mixture was quenched with saturated bicarbonate andextracted with DCM. The organic layer was washed with bicarbonate andbrine solution, dried over anhydrous sodium sulfate and concentrated toobtain the crude product, which was purified by reverse phasechromatography to obtain 60 mg of5-(2-Fluoro-2-pyridin-3-yl-propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.¹H NMR (CDCl₃, freebase) δ (ppm): 8.61 (s, 1H), 8.56 (d, 1H), 7.55 (d,1H), 7.23 (d, 1H), 7.16 (s, 1H), 7.05 (d, 1H), 6.93 (d, 1H), 4.3 (m,2H), 3.8 (dd, 2H), 2.96 (m, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.6 (m, 1H),2.58 (s, 3H), 2.41 (s, 3H), 1.75 (d, 3H). Separation by chiral HPLCprovided enantiomers II-212a-b.

Example 369 Preparation of Compound Nos. II-213 and II-213a-b

1-(8-Hydroxymethyl-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol(700 mg, 1.99 mmol) was dissolved in 70 mL DCM and cooled to 0° C.Diethylaminosulfur trifluoride (800 mg, 4.9 mmol) in DCM (5 mL) wasadded dropwise at the same temperature and stirred for 45 min. Thereaction was monitored by TLC and LCMS. After consumption of startingmaterial, the reaction mixture was quenched with saturated bicarbonateand extracted with DCM. The organic layer was washed with water andbrine solution, dried over anhydrous sodium sulfate and concentrated toobtain the crude product, which was purified by reverse phasechromatography to obtain 14 mg of[5-(2-fluoro-2-pyridin-3-yl-propyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl]-methanol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.6 (s, 1H), 8.57 (d, 1H), 7.6 (d,1H), 7.35 (s, 1H), 7.2 (m, 1H), 7.125 (m, 2H), 4.72 (s, 2H), 4.3 (m,2H), 3.6 (q, 2H), 2.8 (m, 1H), 2.7 (dd, 2H), 2.6 (m, 1H), 2.52 (s, 3H),1.75 (d, 3H). Separation by chiral HPLC provides enantiomers II-213a-b.

Example 370 Preparation of Compound No. II-215

To a stirred solution of6,8,8-trimethyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine(75 mg, 0.348 mmol) in DMF (1.5 mL) was added potassium hydroxide (156mg, 2.784 mmol). After stirring for 10 min at RT, a solution of2-(trifluoromethyl)-5-vinylpyridine (181 mg, 1.046 mmol) in DMF (1.5 mL)was added to the reaction mixture and stirring continued at RT for 24 hand then at 80° C. for 48 h. The progress of reaction was monitored byTLC and LCMS. The reaction mixture was diluted with water and extractedwith EtOAc (3×30 mL). The organic layer was washed with water (2×20 mL),dried over anhydrous sodium sulfate and concentrated to afford crudeproduct, which was purified by reverse phase HPLC. ¹H NMR (CD₃OD, TFAsalt) δ (ppm): 8.48 (s, 1H), 8.3 (d, 1H), 7.97 (d, 1H), 7.9 (d, 1H), 7.7(d, 1H), 7.2 (t, 1H), 4.6 (m, 3H), 4.3 (m, 1H), 3.5 (d, 2H), 3.38 (bs,2H), 3.2 (s, 3H), 1.6 (s, 6H).

Example 371 Preparation of Compound Nos. II-220 and II-220a-b

2,7,8-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (400 mg, 1.86mmol) was dissolved in DMF (4 mL), cooled to 0° C. and sodium hydride(224 mg, 5.60 mmol) was added portionwise at the same temperature.3-(2-methyloxiran-2-yl)pyridine (504 mg, 3.73 mmol) in DMF (1 mL) wasadded to the reaction mixture and allowed to stir at RT for 12 h. Aftercomplete consumption of starting material, the reaction mixture waspoured in to ice water and extracted with EtOAc (3×100 mL). The combinedorganic layer was washed with water (3×50 mL), dried over anhydroussodium sulfate and concentrated to obtain the crude product, which wascrystallized with ether and hexane to obtain 400 mg2-(pyridin-3-yl)-1-(2,7,8-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol.¹H NMR (DMSO, freebase) δ (ppm): 8.60 (s, 1H), 8.4 (d, 1H), 7.7 (d, 1H),7.28 (t, 1H), 7.06 (s, 1H), 7.01 (s, 1H), 4.11 (dd, 2H), 3.41 (m, 2H),2.53 (m, 2H), 2.44 (m, 2H), 2.35 (s, 3H), 2.22 (s, 6H), 1.5 (s, 3H).Separation by chiral HPLC provides enantiomers II-220a-b.

Example 372 Preparation of Compound Nos. II-221 and II-221a-b

To a solution of3-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridine-4-yl-propionitrile(50 mg, 0.1515 mmol) in anhydrous THF (4 mL) was added LiAlH₄ (17 mg,0.4545 mmol) at 0° C. under nitrogen atmosphere. After the addition, thereaction mixture was stirred at RT for 1 h. The progress of the reactionwas monitored by LCMS. After completion of reaction, 0.5 mL of water wasadded dropwise and then 0.5 mL of NaOH solution to quench the excessLiAlH₄. The reaction mixture was evaporated and the crude productpurified by preparative HPLC. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.36 (d,2H), 7.35 (m, 1H), 7.22 (s, 1H), 6.99 (d, 1H), 6.72 b (s, 2H), 4.23 (m,1H), 3.71 (dd, 1H), 3.59 (m, 3H), 3.15 (dd, 1H), 3.07 (dd, 1H), 2.77 (m,2H), 2.47 (s, 3H), 2.45 (s, 3H), 2.1 (m, 3H). Separation by chiral HPLCprovides enantiomers II-221a-b.

Example 373 Preparation of Compound Nos. II-222 and II-222a-b

4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyricacidmethylester(1.5 g, 3.9 mmol) was dissolved in THF (50 mL) and cooled to −78° C.,tert-butyl lithium (16% in pentane) (6 mL, 15.13 mmol) was addeddropwise under nitrogen. The reaction mixture was stirred at −78° C. for90 min. After complete consumption of starting material, the reactionmixture was quenched with ammonium chloride solution and the reactionmixture was allowed to come to RT and extracted with EtOAc (3×100 mL),The combined organic layer was dried over anhydrous sodium sulfate andconcentrated to obtain 1.7 g of crude6-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2,2-dimethyl-5-pyridin-4-yl-hexan-3-one.¹H NMR (CDCl₃, freebase) δ (ppm): 8.41 (d, 2H), 7.31 (d, 1H), 7.19 (s,1H), 7.1 (d, 1H), 6.93 (d, 2H), 4.25 (dd, 1H), 3.9 (t, 2H), 3.8 (m, 1H),3.67 (dd, 1H), 2.87 (m, 3H), 2.71 (m, 2H), 2.51 (s, 3H), 2.42 (s, 3H),2.1 (m, 1H), 1.21 s (9H). Separation by chiral HPLC provides enantiomersII-222a-b.

Example 374 Preparation of Compound Nos. II-223 and II-223a-b

4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-but-3-enoicacidmethyl ester (100 mg, 0.266 mmol) was dissolved in MeOH (10 mL) and 10%dry Pd/C (50 mg) was added and hydrogen gas was purged in to thereaction mixture at RT for 12 h. The reaction was monitored by TLC andLCMS. After consumption of starting material, the reaction mixture wasfiltered through Celite. The filtrate was concentrated to obtain thecrude product, which was recrystallized in ether-hexane to obtained 50mg of4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyricacid methyl ester. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.47 (d, 2H), 7.18(s, 1H), 7.16 (d, 1H), 6.98 (d, 3H), 4.22 (dd, 1H), 4.05 (dd, 1H), 3.7(m, 2H), 3.57 (s, 3H), 3.5 (dd, 1H), 2.74 (m, 3H), 2.71 (m, 2H), 2.49(s, 3H), 2.43 (s, 3H), 2.2 (m, 1H). Separation by chiral HPLC providesenantiomers II-223a-b.

Example 375 Preparation of Compound Nos. II-224 and II-224a-b

A solution of4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyricacid methyl ester (300 mg, 0.795 mmol) in THF (5 mL) was added dropwiseto a solution of LiAlH₄ (93 mg, 2.37 mmol) in THF (10 mL). The reactionmixture was stirred at RT for 30 min. After consumption of startingmaterial, the reaction mixture was cooled to −78° C. 0.2 mL of water and0.2 mL of 15% NaOH solution was added and the reaction mixture wasallowed to come to RT and diluted with THF and filtered. The filtratewas concentrated and the crude product was purified by passing through acolumn of silica gel (100-200 mesh) by using eluent 2% MeOH in DCM toobtain 69 mg of4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butan-1-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.48 (d, 2H), 7.18 (s, 1H), 7.1 (d,1H), 7.01 (d, 2H), 6.97 (d, 1H), 4.2 (dd, 1H), 4.15 (dd, 1H), 3.64 (d,1H), 3.56 (m, 2H), 3.4 (m, 2H), 2.7 (m, 3H), 2.4 (m, 1H), 2.5 (s, 3H),2.43 (s, 3H), 1.94 (m, 2H). Separation by chiral HPLC providedenantiomers II-224a-b.

Example 376 Preparation of Compound Nos. II-225 and II-225a-b

To a compound3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propanoicacid (250 mg, 0.7 mmol) in THF was added LiAlH₄ (81.6 mg, 2.1 mmol) andthe resultant reaction mixture was stirred at RT for 1 h. The progressof the reaction was monitored by TLC and LCMS. The reaction was quenchedby NaOH (0.5 mL), water (3 mL) at 0° C. and extracted with DCM (3×25mL). The combined organic layer was dried on anhydrous sodium sulfateand concentrated under vacuum to obtain the crude product, which wassubjected to reverse phase HPLC to obtain pure compound (30 mg). ¹H NMR(CDCl₃, freebase) δ (ppm): 8.41 (d, 2H), 7.28 b (s, 1H), 7.2 (s, 1H),7.1 (d, 1H), 6.78 (d, 2H), 4.4 bs (OH), 4.3 (m, 1H), 4.0 (m, 1H), 3.62(d, 1H), 3.42 (m, 3H), 3.1 (dd, 1H), 2.7 (m, 3H), 2.46 (m, 1H), 2.43 (s,6H). Separation by chiral HPLC provides enantiomers II-225a-b.

Example 377 Preparation of Compound Nos. II-226 and II-226a-b

4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyricacid methyl ester (400 mg, 1.06 mmol) was dissolved in THF (20 mL) andmethyl magnesium chloride (3 M in THF) (2 mL, 6.3 mmol) was addeddropwise under nitrogen. The reaction mixture was stirred at 60° C. for1 h. After consumption of starting material, the reaction mixture wasquenched with ammonium chloride solution and the reaction mixture wasextracted with EtOAc (3×100 mL). The combined organic layer was driedover anhydrous sodium sulfate and concentrated to obtain 400 mg crude of5-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-methyl-4-pyridin-4-yl-pentan-2-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.43 (d, 2H), 7.16 (s, 1H), 7.14 (d,1H), 6.99 (d, 3H), 4.3 (dd, 1H), 3.98 (d, 1H), 3.9 (dd, 1H), 3.8 (d,1H), 3.5 (m, 1H), 3.15 (dd, 1H), 2.84 (m, 3H), 2.59 (s, 3H), 2.42 (s,3H), 2.3 (dd, 1H), 1.85 (dd, 1H), 1.15 (s, 3H), 1.02 (s, 3H). Separationby chiral HPLC provides enantiomers II-226a-b.

Example 378 Preparation of Compound Nos. II-227 and II-227a-d

6-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2,2-dimethyl-5-pyridin-4-yl-hexan-3-one(400 mg, 0.99 mmol) was dissolved in MeOH (30 mL). Sodium borohydride(263 mg, 6.9 mmol) was added under nitrogen. The reaction mixture washeated at 60° C. for 8 h. After consumption of starting material, thereaction mixture was concentrated and 2N HCl was added (pH-acidic) andextracted with DCM (2×200 mL) for removing impurities. The aqueous layerwas basified with saturated bicarbonate and extracted with DCM. Theorganic layer was dried over anhydrous sodium sulfate and concentratedto obtain 350 mg of6-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2,2-dimethyl-5-pyridin-4-yl-hexan-3-ol.¹H NMR (CDCl₃, freebase) δ (ppm): 8.44 (d, 2H), 7.15 (s, 1H), 7.0 (d,1H), 6.94 (d, 1H), 6.92 (d, 2H), 4.25 (dd, 1H), 4.0 (dd, 1H), 3.64 (d,1H), 3.51 (m, 2H), 2.88 (dd, 1H), 2.73 (t, 1H), 2.58 (m, 1H), 2.48 (s,3H), 2.42 (s, 3H), 2.2 (m, 1H), 2.02 (t, 1H), 1.71 (t, 2H), 0.837 s(9H). Separation by chiral HPLC provided diastereomers II-227a-b.

Example 379 Preparation of Compound Nos. II-229 and II-229a-b

4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyricacid (175 mg, 0.482 mmol) was dissolved in DCM (5 mL), ammonium chloride(51 mg, 0.964 mmol), PYBOP (300 mg, 0.578 mmol) and triethylamine (0.69mL, 4.82 mmol) were added and the reaction mixture was stirred at RT for4 h. The reaction progress was monitored by LC-MS. After completion ofthe reaction, the reaction mixture was concentrated and the crudeproduct was purified by reverse phase chromatography to obtain 45 mg of4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyramideas the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.6 (d, 2H), 7.8 (d,2H), 7.25 (s, 1H), 7.15 (d, 1H), 6.9 (d, 1H), 4.63 (t, 1H), 4.5 (m, 1H),4.4 (m, 1H), 4.3 (dd, 1H), 4.0 (m, 1H), 3.85 (m, 1H), 3.6 (m, 1H), 3.2(m, 1H), 3.1 (s, 3H), 3.0 (m, 1H), 2.9 (m, 2H), 2.4 (d, 3H). Separationby chiral HPLC provides enantiomers II-229a-b.

Example 380 Preparation of Compound Nos. II-230 and II-230a-b

4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyricacid (130 mg, 0.358 mmol) was dissolved in DCM (5 mL), dimethyl aminehydrochloride (57 mg, 0.716 mmol), PYBOP (223 mg, 0.429 mmol) andtriethylamine (0.51 mL, 3.58 mmol) were added and the reaction mixturewas stirred at RT for 4 h. The reaction progress was monitored by LC-MS.After completion of the reaction, the reaction mixture was concentratedand the crude product was purified by reverse phase chromatography toobtain 77 mg of4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-N,N-dimethyl-3-pyridin-4-yl-butyramideas the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.56 (d, 2H), 7.28(d, 2H), 7.19 (s, 1H), 7.17 (d, 1H), 6.94 (d, 1H), 4.63 (dd, 1H), 4.54(dd, 1H), 4.39 (d, 1H), 4.37 (t, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.6 (m,1H), 3.45 (m, 1H), 3.3 (m, 1H), 3.1 (s, 6H), 3.0 (d, 3H), 2.9 (m, 2H),2.8 (d, 3H). Separation by chiral HPLC provides enantiomers II-230a-b.

Example 381 Preparation of Compound Nos. II-231 and II-231a-b

Methanesulfonicacid-4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butylester (200 mg, 0.468 mmol) in 10 mL of aqueous ammonia was heated at100° C. for 1 h. The progress of reaction was monitored by TLC. Afterconsumption of starting material, the reaction mixture was dried and thecrude product was purified by reverse phase chromatography to obtain 33mg of4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butylamineas the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.5 (d, 2H), 7.5 (m,2H), 7.25 (d, 1H), 7.24 (s, 1H), 7.05 (t, 1H), 4.6 (d, 1H), 4.5 (d, 1H),4.3 (m, 1H), 4.23 (t, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.08 (d, 3H), 2.8(m, 2H), 2.7 (m, 2H), 2.4 (s, 3H), 2.25 (m, 1H), 2.2 (m, 1H). Separationby chiral HPLC provides enantiomers II-231a-b.

Example 382 Preparation of Compound Nos. II-232 and II-232a-b

Methanesulfonicacid-4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butylester (200 mg, 0.468 mmol) in 10 mL of 40% aqueous dimethyl amine washeated at 100° C. for 1 h. The progress of reaction was monitored byTLC. After consumption of starting material, the reaction mixture wasdried and the crude product was purified by reverse phase chromatographyto obtain 170 mg of[4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyl]-dimethyl-amineas the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.57 b (s, 2H), 7.65(dd, 2H), 7.23 (d, 1H), 7.21 (s, 1H), 6.99 (d, 1H), 4.62 (m, 1H), 4.48(m, 1H), 4.42 (m, 1H), 4.26 (t, 1H), 3.81 (m, 1H), 3.55 (m, 2H), 3.35(m, 1H), 3.1 (m, 1H), 3.0 (s, 3H), 2.9 (m, 2H), 2.83 (s, 6H), 2.4 (m,1H), 2.38 (s, 3H), 2.29 (m, 1H). Separation by chiral HPLC providesenantiomers II-232a-b.

Example 383 Preparation of Compound No. II-240

Aza-methylcarboline (50 mg, 0.248 mmol), 4-vinylpyridine (49.6 mg, 0.472mmol), tetrabutylammoniumbromide (79.8 mg, 0.248 mmol) were charged in50% solution of sodium hydroxide (2 mL), and the reaction mixture washeated at 95° C. for 1.5 h. The reaction mixture was monitored with TLCand LCMS. The reaction mixture was extracted with EtOAc (2×25 mL). Thecombined organic layer was washed with water (2×20 mL) and dried overanhydrous sodium sulfate. The organic layer was concentrated andpurified through reverse phase chromatography. Yield: 19.20 mg. ¹H NMR(CD₃OD, Free base) δ (ppm): 8.38 (d, 2H), 8.0 (s, 1H), 7.63 (s, 1H), 7.1(d, 2H), 4.4 (t, 2H), 3.8 (s, 2H), 3.15 (t, 2H), 3.0 (t, 2H), 2.75 (t,2H), 2.61 (s, 3H), 2.4 (s, 3H).

Example 384 Preparation of Compound Nos. II-241 and II-241a-b

Aza-carboline (100 mg, 0.53 mmol) was dissolved in DMF (8 mL). Sodiumhydride (38 mg, 1.59 mmol) was added at 0-10° C. and stirred at the sametemperature for 15 min. 4-(oxiran-2-yl)pyridine (254 mg, 2.12 mmol) inDMF (2 mL) was added dropwise into the reaction mixture and the mixturewas stirred at RT for 16 h. The reaction was monitored by LCMS. Afterconsumption of starting material, the reaction mixture was quenched withice cold water (4 mL) and solvent was evaporated to obtain the crudeproduct, which was purified by reverse phase column chromatography toobtain 10 mg of product. ¹H NMR (CD₃OD, freebase) δ (ppm): 8.41 (d, 2H),8.19 (d, 1H), 7.73 (s, 1H), 7.36 (d, 2H), 7.06 (m, 1H), 5.04 (t, 1H),4.6 (m, 1H), 4.33 (m, 2H), 3.76 (dd, 2H), 2.9 (m, 4H), 2.5 (s, 3H).Separation by chiral HPLC provides enantiomers II-241a-b.

Example 385 Preparation of Compound No. II-242 and II-242a-b

Aza-carboline (300 mg, 1.60 mmol) was dissolved in DMF (8 mL). Sodiumhydride (153 mg, 6.4 mmol) was added at 0-10° C. and stirred at the sametemperature for 15 min., 4-(oxiran-2-yl)pyridine (769 mg, 6.41 mmol) inDMF (2 mL) was added dropwise into the reaction mixture and the mixturewas stirred at RT for 16 h. The reaction was monitored by LCMS. Afterconsumption of starting material, the reaction mixture was quenched withice cold water (4 mL) and solvent was evaporated to obtain the crudeproduct, which was purified by reverse phase column chromatography toobtain 8 mg of product. ¹H NMR (CD₃OD, freebase) δ (ppm): 8.5 (s, 1H),8.43 (d, 2H), 8.01 (d, 1H), 7.4 (d, 1H), 7.38 (d, 2H), 5.07 (t, 1H), 4.4(m, 2H), 3.68 (s, 2H), 3.3 (s, 2H), 2.85 (m, 4H), 2.45 (s, 3H).Separation by chiral HPLC provides enantiomers II-242a-b.

Example 386 Preparation of Compound Nos. II-243 and II-243a-b

5-[2-(9-Methyl-1,2,3,4,5,10c-hexahydro-3a,6,7-triaza-cyclopenta[c]fluoren-6-yl)-ethyl]-pyridine-2-carboxylicacid (400 mg, 1.063 mmol) was dissolved in 15 mL DCM and cooled at 0° C.Oxalyl chloride (669 mg, 5.315 mmol) and catalytic amount of DMF wasadded and the reaction mixture was stirred at RT for 1 h. The reactionwas monitored by LCMS. The reaction mixture was concentrated and aqueousammonia was added at 0° C. The reaction mixture was warmed to RT andstirred for 1 h. The reaction mixture was concentrated to obtain thecrude product that was purified by reverse phase chromatography toobtain 2.5 mg of5-[2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6,7-triaza-cyclopenta[c]fluoren-6-yl)-ethyl]-pyridine-2-carboxylicacid amide as the TFA salt. ¹H NMR TFA:—CD₃OD: 8.2 (s, 2H), 7.95 (d,1H), 7.8 (s, 1H), 7.6 (d, 1H), 5.0 (t, 1H), 4.6 (m, 2H), 3.62 (m, 1H),3.5 (m, 2H), 3.3 (m, 3H), 2.8 (d, 1H), 2.63 (m, 2H), 2.4 (s, 3H), 2.2(m, 2H), 2.1 (m, 1H). Separation by chiral HPLC provides enantiomersII-243a-b.

Example 387 Preparation of Compound Nos. II-244 and II-244a-b

9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene(250 mg, 1.10 mmol), 4-vinyl-pyridine (347 mg, 3.30 mmol), tetrabutylammonium bromide (355 mg, 1.10 mmol) were charged in a screw cap bottleand a 60% solution of sodium hydroxide (5 mL) was added and heated to100° C. for 12 h. The reaction was monitored by TLC and LCMS. Thereaction mixture was diluted with 25 mL of water and extracted withEtOAc (2×50 mL). The combined organic extracts were washed with water(25 mL), dried over anhydrous sodium sulfate and concentrated. Theresultant crude product was purified by reverse phase chromatography toobtain 85 mg of9-methyl-6-(2-pyridin-4-yl-ethyl)-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluoreneas the formate salt (the product was a racemate which was purified bychiral prep HPLC to obtain product II-244a & product II-244b as thefreebase). ¹H NMR (CDCl₃, freebase) δ (ppm): 8.45 (d, 2H), 8.17 (s, 1H),7.56 (s, 1H), 6.91 (d, 2H), 4.5 (m, 1H), 4.42 (t, 1H), 4.35 (m, 1H),3.26 (m, 2H), 3.16 (m, 5H), 2.81 (m, 1H), 2.45 (m, 1H), 2.41 (s, 3H),2.1 (m, 2H), 1.9 (m, 1H). Separation by chiral HPLC provided enantiomersII-244a-b.

Example 388 Preparation of Compound Nos. II-245 and II-245a-b

A suspension of azabicyclic carboline (0.2 g, 0.8 mmol), vinylpyrazine(0.375 g, 3.5 mmol), and tetrabutylammoniumbromide (0.855 g, 2.6 mmol)in 50% NaOH solution (2 mL) was heated at 100° C. for overnight. Thereaction mixture diluted with EtOAc (50 mL), organic layer washed withwater (20 mL), dried over anhydrous sodium sulfate, and concentratedunder vacuum to obtain the crude product that was purified by reversephase HPLC to obtain 2.4 mg of desired compound. ¹H NMR (CD₃OD, TFAsalt) δ (ppm): 8.48 (s, 1H), 8.39 (s, 1H), 8.1 (s, 1H), 8.06 (s, 1H),7.7 (s, 1H), 5.1 (m, 1H), 4.64 (t, 2H), 3.7 (m, 4H), 3.03 (t, 2H), 2.7(m, 2H), 2.45 (s, 3H), 2.15 (m, 4H). Separation by chiral HPLC providesenantiomers II-245a-b.

Example 389 Preparation of Compound No. II-246

To a solution of7,10-dichloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (200mg, 0.746 mmol) in DMF (2 mL), sodium hydride (90 mg, 2.25 mmol) wasadded. After stirring at 60° C. for 30 min.,2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (543 mg, 1.86mmol) was added to the reaction mixture and the reaction mixture wasstirred at the same temperature for min. The progress of reaction wasmonitored by TLC and LCMS. The reaction mixture was quenched with waterand extracted with EtOAc. The organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated to obtain the residuethat was purified by reverse phase HPLC to obtain7,10-dichloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(2-(6-methylpyridin-3-yl)ethyl)azepino[4,5-b]indole.¹H NMR TFA:—CD₃OD: 8.4 (s, 1H), 8.1 (d, 1H), 7.75 (d, 1H), 7.0 (q, 2H),4.8 (m, 1H), 4.0 (m, 1H), 3.8 (m, 2H), 3.4 (m, 3H), 3.3 (m, 2H), 3.2 (t,3H), 3.0 (s, 3H), 2.7 (s, 3H).

Example 390 Preparation of Compound No. II-247

To a solution of9-bromo-6-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (500mg, 1.67 mmol) in DMF (5 mL), sodium hydride (200 mg, 5.0 mmol) wasadded. After stirring at 60° C. for 30 min.,2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (1.2 g, 4.2 mmol)was added to the reaction mixture and stirred at the same temperaturefor 1 h. The progress of reaction was monitored by TLC and LCMS. Thereaction mixture was quenched with water and extracted with EtOAc. Theorganic layer was washed with water, dried over anhydrous sodium sulfateand concentrated to obtain the crude product, which was purified byreverse phase HPLC to obtain the9-bromo-6-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.39 (s, 1H), 8.12 (d, 1H), 7.66 (d,1H), 7.26 (d, 1H), 7.1 (d, 1H), 4.67 (m, 4H), 3.7 (m, 2H), 3.27 (t, 2H),3.18 (m, 2H), 3.15 (s, 3H), 2.69 (s, 3H).

Example 391 Preparation of Compound No. II-248

To a solution of9-chloro-6-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(500 mg, 2.1 mmol) in DMF (5 mL), sodium hydride (252 mg, 6.3 mmol) wasadded. After stirring at 60° C. for 30 min.,2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (1.5 g, 5.25mmol) was added to the reaction mixture and stirred at the sametemperature for 1 h. The progress of reaction was monitored by TLC andLCMS. The reaction mixture was quenched with water and extracted withEtOAc. The organic layer was washed with water, dried over anhydroussodium sulfate and concentrated to obtain the crude product, which waspurified by reverse phase HPLC to obtain the9-chloro-6-fluoro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole.¹H NMR (CD₃OD, TFA) δ (ppm): 8.37 (s, 1H), 8.12 (d, 1H), 7.73 (d, 1H),7.02 (dd, 1H), 6.86 (t, 1H), 5.1 (m, 1H), 4.57 (t, 2H), 4.56 (m, 1H),3.85 (m, 1H), 3.6 (m, 1H), 3.27 (m, 3H), 3.2 m (2, H), 3.1 (s, 3H), 2.69(s, 3H).

Example 392 Preparation of Compound No. II-249

To a solution of5,8-dichloro-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole (200 mg,0.78 mmol) in DMF (2 mL), sodium hydride (94 mg, 2.36 mmol) was added.After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl4-methylbenzenesulfonate (572 mg, 1.96 mmol) was added to the reactionmixture and stirred at the same temperature for 40 min. The progress ofreaction was monitored by TLC and LCMS. The reaction mixture wasquenched with water and extracted with EtOAc. The organic layer waswashed with water, dried over anhydrous sodium sulfate and concentratedto get the residue that was purified by reverse phase HPLC to obtain the5,8-dichloro-2,3,4,9-tetrahydro-2-methyl-9-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[3,4-b]indole.¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.43 (s, 1H), 8.18 (d, 1H), 7.74 (d,1H), 7.09 (d, 1H), 7.04 (d, 1H), 4.79 (t, 2H), 4.65 b (s, 1H), 3.62 b(s, 1H), 3.5 (m, 2H), 3.35 (m, 2H), 3.25 (t, 2H), 3.16 (s, 3H), 2.75 (s,3H).

Example 393 Preparation of Compound No. II-250

To a solution of6,9-difluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (550 mg,2.42 mmol) in DMF (3.5 mL) was added sodium hydride (300 mg, 7.4 mmol).After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl4-methylbenzenesulfonate (1.8 g, 6.1 mmol) was added to the reactionmixture, which was stirred at the same temperature for 1 h. The progressof reaction was monitored by TLC and LCMS. The reaction mixture wasquenched with water and extracted with EtOAc. The organic layer waswashed with water, dried over anhydrous sodium sulfate and concentrated.The residue was purified by reverse phase HPLC (540 mg, TFA salt). ¹HNMR (CD₃OD, TFA salt) δ (ppm): 8.35 (s, 1H), 8.13 (d, 1H), 7.73 (d, 1H),6.7 (m, 2H), 4.8 (m, 1H), 4.57 (t, 2H), 4.5 (m, 1H), 3.9 (m, 1H), 3.6(m, 1H), 3.35 (m, 2H), 3.19 (m, 2H), 3.13 (s, 3H), 2.69 (s, 3H).

Example 394 Preparation of Compound No. II-251

To a solution of6,9-dibromo-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (800 mg,2.32 mmol) in DMF (5 mL) was added sodium hydride (0.279 g, 6.9 mmol).After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl4-methylbenzenesulfonate (1.7 g, 5.8 mmol) was added to the reactionmixture, which was stirred at the same temperature for 1 h. The progressof reaction was monitored by TLC and LCMS. The reaction mixture wasquenched with water and extracted with EtOAc. The organic layer waswashed with water, dried over anhydrous sodium sulfate and concentrated.The residue was purified by reverse phase HPLC (460 mg, TFA salt). ¹HNMR (CD₃OD, TFA salt) δ (ppm): 8.46 (s, 1H), 8.18 (d, 1H), 7.72 (d, 1H),7.28 (d, 1H), 7.18 (d, 1H), 5.2 (m, 2H), 4.6 (m, 2H), 3.9 (m, 1H), 3.6(m, 1H), 3.2 (m, 4H), 3.15 (s, 3H), 2.71 (s, 3H).

Example 395 Preparation of Compound No. II-252

To a solution of6-bromo-9-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (500mg, 1.67 mmol) in DMF (4 mL) was added sodium hydride (120 mg, 5.0mmol). After stirring at 60° C. for 30 min.,2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (1.2 g, 4.19mmol) was added to the reaction mixture, which was stirred at the sametemperature for 1 h. The progress of the reaction was monitored by TLCand LCMS. The reaction mixture was quenched with water and extractedwith EtOAc. The organic layer was washed with water, dried overanhydrous sodium sulfate and concentrated. The residue was purified byreverse phase HPLC (279 mg, TFA salt). ¹H NMR (CD₃OD, TFA salt) δ (ppm):8.43 (s, 1H), 8.14 (d, 1H), 7.7 (d, 1H), 7.35 (d, 1H), 7.03 (d, 1H), 5.0(m, 2H), 4.6 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.27 (t, 2H), 3.22 (t,2H), 3.14 (s, 3H), 2.7 (s, 3H).

Example 396 Preparation of Compound No. II-253

To a solution of6-chloro-9-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(500 mg, 2.1 mmol) in DMF (5 mL) was added sodium hydride (252 mg, 6.3mmol). After stirring at 60° C. for 30 min.,2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (1.5 g, 5.25mmol) was added to the reaction mixture, which was stirred at the sametemperature for 1 h. The progress of the reaction was monitored by TLCand LCMS. The reaction mixture was quenched with water and extractedwith EtOAc. The organic layer was washed with water, dried overanhydrous sodium sulfate and concentrated. The residue was purified byreverse phase HPLC (463 mg, TFA salt). ¹H NMR (CD₃OD, TFA salt) δ (ppm):8.42 (s, 1H), 8.15 (d, 1H), 7.7 (d, 1H), 7.1 (dd, 1H), 6.8 (t, 1H), 4.8(m, 2H), 4.5 (m, 2H), 3.8 (m, 1H), 3.6 (m, 1H), 3.3 (t, 2H), 3.2 (t,2H), 3.1 (s, 3H), 2.7 (s, 3H).

Example 397 Preparation of Compound Nos. II-255 and II-255a-b

3-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxy-2-(pyridin-4-yl)propanenitrile.diHClsalt (500 mg, 1.19 mmol) was dissolved in 500 mL Ethanol. The solutionwas passed through H-Cube as condition 70 mbar at 70° C. (Ra/Ni ascatalyst). The product formation observed by LCMS. The solvent wasconcentrated under reduced pressure. The crude product was purified byreverse phase column chromatography to obtain1-amino-3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol(31 mg) as the TFA salt. ¹H NMR (CDCl₃, freebase) δ (ppm): 8.61 (d, 2H),7.42 (d, 2H), 7.23 (d, 1H), 7.18 (s, 1H), 6.95 (d, 1H), 4.17 (dd, 2H),3.68 (q, 2H), 3.2 (d, 1H), 3.1 (m, 1H), 2.76 (m, 3H), 2.63 (m, 1H), 2.55(s, 3H), 2.43 (s, 3H). Separation by chiral HPLC provided enantiomersII-255a-b.

Example 398 Preparation of Compound Nos. II-256 and II-256a-b

A solution of alcohol (2 g, 6.2 mmol) in THF (150 mL) was cooled at −78°C., NaH (0.3 g, 12.4 mmol, 60% dispersion in mineral oil) was added andthe reaction mixture was stirred at the same temperature for 30 min.Methyl acrylate (2.1 g, 31.1 mmol) was added slowly and the reactionmixture was stirred at −78° C. for 1 h and at RT for further 2 h. Thereaction mixture was quenched with water (60 mL) and extracted withEtOAc (2×60 mL). The combined organic layer was washed with brine (50mL), dried over anhydrous Sodium sulfate. Removal of solvent underreduced pressure gave crude product that was purified by columnchromatography using neutral alumina and 1-2% MeOH-DCM system as eluentto give 0.8 g pure desired ester. To a solution of ester (0.2 g, 0.49mmol) in MeOH (5 mL) was added 1 N LiOH (1 mL) at RT and the reactionmixture was stirred at 50° C. for 1 h. The reaction mixture wasconcentrated to dryness under reduce pressure to give crude productwhich was purified by reverse phase preparative HPLC to give 108 mg pureproduct. ¹H NMR (CD₃OD, TFA) δ (ppm): 8.66 (d, 2H), 7.8 (d, 2H), 7.23(s, 1H), 7.1 (d, 1H), 7.0 & 6.9 (d, 1H), 4.8 (m, 1H), 4.7 (m, 1H), 4.4(m, 3H), 3.85 (m, 1H), 3.6 (m, 2H), 3.45 (m, 1H), 3.24 (m, 4H), 3.12 (s,3H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomersII-256a-b.

Example 399 Preparation of Compound Nos. II-257 and II-257a-b

A mixture of2,8-dimethyl-5-((2-(pyridin-3-yl)oxiran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.3 mmol) in 20% aq. TFA (2 mL) was stirred at RT overnight.The reaction mixture was neutralized with saturated sodium bicarbonatesolution and extracted with EtOAc (2×30 mL) to remove the impurities.The aqueous layer was lyophilized to obtain the crude product that waspurified by reverse phase HPLC to obtain 5 mg of3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propane-1,2-diolas the TFA salt. ¹H NMR (CD₃OD, TFA) δ (ppm): 8.75 (s, 1H), 8.6 (m, 2H),7.83 (m, 1H), 7.25 (s, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 4.62 (d, 1H), 4.45(dd, 2H), 4.3 (t, 1H), 4.05 (t, 1H), 3.8 (m, 2H), 3.5 (m, 3H), 3.1 (s,3H), 2.3 (s, 3H). Separation by chiral HPLC provides enantiomersII-257a-b.

Example 400 Preparation of Compound Nos. II-258 and II-258a-b

3-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propanoicacid (20 mg, 0.057 mmol) was charged in pyridine (0.5 mL) undernitrogen. DMAP (9.73 mg, 0.08 mmol) and (Boc)₂O (14 mg, 0.069 mmol) wereadded into it. The reaction mixture was stirred at 60° C. for 30 min andallowed to come to RT. Tert-butanol (84.81 mg, 1.146 mmol) was addeddropwise and the reaction mixture was stirred at RT for 1 h. 1M citricacid (5 mL) was added and reaction mixture was then washed with DCM (5mL). The organic layer was concentrated and the crude product waspurified by reverse phase HPLC to obtain tert-butyl3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propanoate(15.4 mg, TFA salt). ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.49 (d, 2H),7.53 (d, 2H), 7.3 (t, 1H), 7.24 (s, 1H), 7.05 (m, 1H), 5.5 (m, 1H), 4.6(t, 1H), 4.24 (t, 1H), 3.8 (m, 3H), 3.3 (m, 2H), 3.13 (d, 2H), 2.89 (m,1H), 2.77 (m, 1H), 2.4 (s, 3H), 1.39 s (9H). Separation by chiral HPLCprovides enantiomers II-258a-b.

Example 401 Preparation of Compound Nos. II-259 and II-259a-b

2,8-Dimethyl-5-((2-(pyridin-4-yl)oxiran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.3 mmol) was added to 2M dimethyl amine solution in THF (5 mL)and the reaction mixture was allowed to stir at 60° C. overnight. Theprogress of reaction was monitored by LCMS. The solvent was removedunder reduced pressure to obtain a crude oily product that was purifiedby reverse phase HPLC to afford 5 mg of1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(dimethylamino)-2-(pyridin-4-yl)propan-2-olas the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.58 (d, 2H), 7.81(m, 2H), 7.18 (d, 1H), 7.05 (m, 1H), 6.91 (m, 1H), 4.63 (m, 1H), 4.51(s, 2H), 4.27 (d, 1H), 4.18 (m, 2H), 3.58 (m, 2H), 3.48 (m, 1H), 3.1 (s,6H), 2.89 (m, 1H), 2.8 (s, 3H), 2.35 (s, 3H). Separation by chiral HPLCprovides enantiomers II-259a-b.

Example 402 Preparation of Compound Nos. II-260 and II-260a-b

Methanesulfonic acid2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester(1.0 g, 3.5 mmol) was dissolved in 70% cyclopropylamine in water (50 mL)and heated at 90° C. for 18 h. The reaction mixture was concentrated toobtain the crude product that was purified by reverse phasechromatography to obtain 300 mg ofcyclopropyl-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-amine.¹H NMR (CDCl₃, Free base) δ (ppm): 8.52 (d, 2H), 7.18 (s, 1H), 7.14 (d,1H), 7.13 (d, 2H), 6.99 (d, 1H), 4.22 (m, 2H), 3.98 (dd, 1H), 3.76 (d,1H), 3.70 (d, 1H), 2.85 (m, 1H), 2.74 (m, 2H), 2.55 (s, 3H), 2.44 (s,3H), 2.36 (m, 2H), 0.33 (m, 2H), 0.23 (m, 2H). Separation by chiral HPLCprovided enantiomers II-260a-b.

Example 403 Preparation of Compound Nos. II-261 and II-261a-d

Methanesulfonicacid2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyrazin-2-yl-ethylester (280 mg, 0.65 mmol) was dissolved in 3 mL DMF, sodium azide (64mg, 0.98 mmol) was added and heated at 90° C. for 1 h. The reactionmixture was monitored by LCMS. After consumption of starting material,the reaction mixture was cooled to RT, diluted with water (3 mL) andconcentrated to obtain the crude product, which was purified by reversephase chromatography to obtain 60 mg of6-(2-azido-2-pyrazin-2-yl-ethyl)-9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene.¹H NMR (CDCl₃, freebase) δ (ppm): 8.65 (d, 1H), 8.60 (s, 1H), 8.50 (s,1H), 7.8 (d, 1H), 7.22 (d, 1H), 7.09 (t, 1H), 5.1 (m, 1H), 4.8 (m, 1H),4.6 (dd, 1H), 4.3 (m, 1H), 3.45 (m, 3H), 2.97 (m, 2H), 2.84 (m, 2H), 2.6(m, 1H), 2.45 (d, 3H), 2.2 (m, 1H), 1.9 m (1′H). Separation by chiralHPLC provided enantiomers II-261a-b.

Example 404 Preparation of Compound Nos. II-262 and II-262a-b

3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propanenitrile(80 mg, 0.24 mmol) in conc. HCl (2 mL) was heated at 80° C. for 1 h. Thereaction mixture was concentrated to obtain a residue that was purifiedby reverse phase chromatography to obtain 5.3 mg of3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propanoicacid as the free base. ¹H NMR (CD₃OD, freebase) δ (ppm): 8.1 (d, 2H),7.3 (d, 1H), 7.13 (s, 1H), 6.98 (d, 1H), 6.8 (d, 2H), 4.09 (s, 2H), 3.6(dd, 1H), 3.4 (m, 3H), 2.9 (m, 2H), 2.8 (s, 3H), 2.39 (s, 3H), 2.32 (m,1H). Chiral HPLC provides enantiomers II-262a and II-262b.

Example 405 Preparation of Compound Nos. II-263 and II-263a-b

To a solution of tert-butanol (4 mL) containing crushed KOH (20.36 mg,0.363 mmol) was added3-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridine-4-yl-propionitrile(40 mg, 0.121 mmol) and the resultant reaction mixture was stirred at80° C. for 90 min. The progress of the reaction was monitored by TLC andLCMS. After completion of the reaction, the tert-butanol was evaporatedunder vacuum and resultant reaction mixture was purified by preparativeHPLC to obtain the desired compound (15 mg). ¹H NMR (CDCl₃, freebase):8.32 (d, 2H), 7.25 (d, 2H), 7.15 (d, 1H), 7.01 (d, 1H), 6.63 (d, 1H),4.8 (d, 1H), 3.77 (m, 2H), 3.39 (t, 2H), 2.8 (m, 1H), 2.7 (m, 1H), 2.5(m, 1H), 2.47 (s, 3H), 2.45 (s, 3H), 2.3 (m, 1H). Chiral HPLC providesenantiomers II-263a and II-263b.

Example 406 Preparation of Compound Nos. II-264 and II-264a-b

2,8-Dimethyl-5-((2-(pyridin-3-yl)oxiran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(100 mg, 0.3 mmol) was dissolved in MeOH (2 mL) and aq. ammonia (2 mL)and the reaction mixture was allowed to stir at RT for 24 h. Theprogress of reaction was monitored by LCMS. The volatiles were removedunder reduced pressure to obtain a crude oily product that was purifiedby reverse phase HPLC to afford 7 mg of1-amino-3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-olas TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.65 (m, 2H), 8.43 (dd,1H), 7.75 (m, 1H), 7.18 (d, 1H), 6.88 (m, 2H), 4.67 (d, 1H), 4.55 (m,2H), 4.29 (t, 1H), 3.90 (m, 2H), 3.69 (m, 1H), 3.5 (m, 2H), 3.1 (m, 1H),3.11 (s, 3H), 2.34 (s, 3H). Separation by chiral HPLC providesenantiomers II-264a-b.

Example 407 Preparation of Compound Nos. II-265 and II-265a-b

2,8-Dimethyl-5-((2-(pyridin-3-yl)oxiran-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(200 mg, 0.6 mmol) was added to 2M dimethylamine solution in THF (5 mL)and the reaction mixture was allowed to stir at 40° C. overnight. Theprogress of reaction was monitored by LCMS. The solvent was removedunder reduced pressure to obtain a crude oily product that was purifiedby reverse phase HPLC to afford 50 mg of1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(dimethylamino)-2-(pyridin-3-yl)propan-2-olas the TFA salt. ¹H NMR (CDCl₃, Free base) δ (ppm): 8.74 (s, 1H), 8.50(d, 1H), 7.79 (d, 1H), 7.25 (dd, 1H), 7.16 (s, 1H), 7.1 (d, 1H), 6.97(d, 1H), 4.08 (m, 2H), 3.83 (dd, 2H), 2.98 (m, 4H), 2.74 (d, 2H), 2.70(s, 3H), 2.42 (s, 3H), 1.98 (s, 6H). Separation by chiral HPLC providedenantiomers II-265a-b.

Example 408

Compounds III-1, III-53 and III-223-224 were synthesized as described inPCT publication WO2009/055828. Compounds III-2-3 were synthesized asdescribed in PCT publication WO2009/120720. Compounds III-4-9 weresynthesized as described in PCT publication WO2009/120717. CompoundsIII-10-46, III-209-220 and III-320-352 were synthesized as described inPCT publication WO2010/051503. Compounds III-47-51 were synthesized asdescribed in PCT publication WO2010/127177. Compounds III-52 andIII-225-253 were synthesized as described in PCT publicationWO2010/019417. Compounds III-54-58, III-353-355 and III-357 weresynthesized as described in PCT publication WO2011/038163. CompoundsIII-59-61, III-356 and III-358-361 were synthesized as described in PCTpublication WO2011/038161. Compounds III-62-98, III-187-197 andIII-256-258 were synthesized as described in PCT publicationWO2011/038162. Compounds III-99-138, III-198-208, III-221 andIII-289-319 were synthesized as described in PCT publicationWO2011/038164.

Example 409

Compounds IV-2, IV-4-7 and IV-10 were synthesized as described in PCTpublication WO2011/038161. Compounds IV-1, IV-3, IV-9, IV-11-92,IV-94-208 and IV-211-244 can be synthesized using similar conditions tothose described in both Examples 410-412 below, and in PCT publicationWO2011/038161.

Example 410 Preparation of Compound Nos. IV-8 and IV-8a-b

To a solution of10-methyl-1,2,3,4,5,6,7,11c-octahydro-4-a,7,8-triaza-benzo[c]fluorene(150 mg, 0.622 mmol) in DMF (2 mL) were added sodium hydride (75 mg,1.86 mmol) and a solution of toluene-4-sulfonic acid2-(6-methyl-pyridin-3-yl)-ethyl ester (544 mg, 1.86 mmol) in DMF (2 mL)at 0° C. The reaction mixture was stirred at RT for 1 h. The progress ofreaction was monitored by TLC and LCMS. The reaction mixture was pouredinto ice-cold water and extracted with EtOAc (2×50 mL). The combinedorganic layer was washed with water (5×25 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by reverse phase chromatography to yield compound 8 (140 mg).This product was further purified by chiral preparative HPLC to givecompounds 8a and 8b. Compound 8a: ¹HNMR (CDCl₃, freebase) δ (ppm): 8.21(s, 1H), 8.07 (s, 1H), 7.6 (s, 1H), 7.21 (d, 1H), 7.0 (d, 1H), 4.3 (m,2H), 3.28 (d, 1H), 3.08 (m, 1H), 3.0 (m, 4H), 2.54 (m, 1H), 2.54 (s,3H), 2.5 (m, 1H), 2.4 (m, 1H), 2.4 (s, 3H), 2.3 (d, 1H), 1.9 (m, 1H),1.72 (m, 2H), 1.5 (q, 2H). Compound 8b: ¹HNMR (CDCl₃, freebase) δ (ppm):8.21 (s, 1H), 8.07 (s, 1H), 7.6 (s, 1H), 7.21 (d, 1H), 7.0 (d, 1H), 4.3(m, 2H), 3.28 (d, 1H), 3.08 (m, 1H), 3.0 (m, 4H), 2.54 (m, 1H), 2.54 (s,3H), 2.5 (m, 1H), 2.4 (m, 1H), 2.4 (s, 3H), 2.3 (d, 1H), 1.9 (m, 1H),1.72 (m, 2H), 1.5 (q, 2H).

Example 411 Preparation of Compound Nos. IV-209 and IV-209a-d

9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene(600 mg, 2.643 mmol) was dissolved in DMF (18 mL), and cooled to 0° C.Potassium tert-butoxide (444 mg, 3.964 mmol) was added and stirred for 5min. 4-Oxiranyl-pyridine (639 mg, 5.286 mmol) in DMF (3 mL) was addeddropwise into the reaction mixture and the mixture was stirred at RT for12 h. The reaction was monitored by TLC and LCMS. After consumption ofstarting material, the reaction mixture was quenched with ice cold water(100 mL) and extracted with EtOAc (2×100 mL). The combined organic layerwas washed with water (4×70 mL), dried over anhydrous sodium sulfate andconcentrated to obtain the crude product, which was purified by reversephase chromatography to obtain 400 mg of2-(9-Methyl-1,2,3,4,5,10c-hexahydro-3a,6,7-triaza-cyclopenta[c]fluoren-6-yl)-1-pyridin-4-yl-ethanol.¹H NMR (CD₃OD, HCl salt) δ (ppm): 8.8 (d, 2H), 8.2 (d, 2H), 8.1 (s, 1H),7.9 (s, 1H), 5.38 (m, 1H), 5.09 (t, 1H), 4.68 (dd, 2H), 4.4 (m, 1H),3.75 (m, 4H), 3.43 (m, 2H), 2.7 (m, 2H), 2.46 (s, 3H), 2.2 (m, 3H).Separation by chiral HPLC provided diastereomers IV-209a-d.

Example 412 Preparation of Compound Nos. IV-210 and IV-210a-d

Chloroaza carboline (500 mg, 2.02 mmol) was dissolved in DMF (8 mL),sodium hydride (404 mg, 10.12 mmol) was added at 0-10° C. and stirred atthe same temperature for 15 min. 3-(2-Methyloxiran-2-yl)pyridine (546 g,4.04 mmol) was added dropwise into the reaction mixture and the mixturewas stirred at RT for 16 h. The reaction was monitored by TLC and LCMS.After consumption of starting material, the reaction mixture wasquenched with ice cold water (100 mL) and extract with EtOAc (200 mL).The organic layer was washed with water (5×50 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to obtain thecrude product, which was purified by crystallization using Diethyl etherto obtain 200 mg of product. ¹H NMR (CD₃OD, HCl salt): 8.8 (s, 1H), 8.6(d, 2H), 7.88 (s, 2H), 7.84 (d, 1H), 4.99 (m, 2H), 4.4 (d, 1H), 3.78 (m,2H), 3.4 (m, 2H), 3.4 (m, 2H), 2.7 (m, 1H), 2.2 (m, 3H), 1.83 (s, 3H).Separation by chiral HPLC provided diastereomers IV-210a-d.

Example 413

Compound Nos. V-4 to V-13, V-16 to V-17 and V-19 to V-20 can besynthesized using similar conditions to those described in Examples414-422 below.

Example 414 Preparation of Compound Nos. V-1 and V-1a-b

To a solution of2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethylmethanesulfonate (900 mg, 2.18 mmol) in DMF (10 mL) was added sodiumazide (212.5 mg, 3.2 mmol) and the reaction mixture was stirred at 100°C. for 1 h. The reaction mixture was diluted with water and extractedwith EtOAc. The organic layer was washed with water, dried overanhydrous sodium sulfate and concentrated under reduced pressure toyield5-(2-azido-2-(pyridin-4-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole(650 mg). The resulting racemate was purified and resolved by chiralpreparative HPLC. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.8 (d, 2H), 8.0 (d,2H), 7.31 (d, 1H), 7.3 (s, 1H), 7.04 (d, 1H), 5.45 (m, 1H), 4.7 (d, 1H),4.59 (t, 1H), 4.4 (m, 2H), 3.9 (d, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.2(m, 1H), 3.1 (s, 3H), 2.4 (s, 3H).

Example 415 Preparation of Compound Nos. V-2 and V-2a-b

To a solution of2-(2,8-dimethyl-6-aza-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethylmethanesulfonate (300 mg, 0.724 mmol) in DMF (4 mL) was added sodiumazide (70.65 mg, 1.08 mmol) and the reaction mixture was stirred at 100°C. for 1 h. The progress of reaction was monitored by NMR. The reactionmixture was diluted with water and extracted with EtOAc. The organiclayer was thoroughly washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to yield9-(2-azido-2-(pyridin-4-yl)ethyl)-3,6-dimethyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine(160 mg). ¹H NMR (CDCl₃, freebase) δ (ppm): 8.6 (d, 2H), 8.07 (s, 1H),7.55 (s, 1H), 7.27 (d, 2H), 5.23 (m 1H), 4.37 (dd, 1H), 4.19 (m, 1H),3.62 (dd, 2H), 2.88 (m, 2H), 2.82 m, 2H), 2.56 (s, 3H), 2.42 (s, 3H).Separation by chiral HPLC provided enantiomers V-2a-b.

Example 416 Preparation of Compound Nos. V-3 and V-3a-b

5-(2-Chloro-2-(pyridin-3-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(crude) (700 mg) was dissolved in DMF (4 mL). Sodium azide (975 mg, 15mmol) was added and reaction mixture was stirred at 80° C. for 1 h. Thereaction mixture was diluted with water, basified with aqueous NaHCO₃solution and was extracted with EtOAc (200 mL). The organic layer waswashed with water (6×50 mL), dried over anhydrous sodium sulfate andevaporated in vacuo to obtain the crude product that was purified byreverse phase HPLC to obtain 1 mg of5-(2-azido-2-(pyridin-3-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoleas the TFA salt. ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.56 (m, 2H), 8.11(dd, 1H), 7.6 (t, 1H), 7.2 (s, 1H), 6.85 (m, 2H), 4.67 (d, 1H), 4.47 (d,1H), 4.39 (s, 2H), 3.84 (m, 1H), 3.48 (m, 1H), 3.34 (m, 1H), 3.12 (s,3H), 3.12 (m, 1H), 2.36 (s, 3H), 2.03 (s, 3H). Separation by chiral HPLCprovides enantiomers V-3a-b.

Example 417 Preparation of Compound Nos. V-14 and V-14a-b

To a solution of1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol(200 mg, 0.597 mmol) in DMF (5 mL) was added potassium carbonate (412mg, 2.98 mmol). After stirring for 5 min at RT, ethyl bromoacetate (200mg, 1.19 mmol) was added into the reaction mixture, which was stirred atRT for 2 h. The progress of reaction was monitored by LCMS. The reactionwas quenched with water and extracted with EtOAc. The aqueous layer wasconcentrated and residue was purified by reverse HPLC to yield2-((1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-yl)oxy)aceticacid (80 mg). The resulting racemate was purified and resolved by chiralpreparative HPLC. ¹H NMR (CD₃OD, freebase) δ (ppm): 8.5 (d, 1H), 8.36(s, 1H), 7.8 (dd, 1H), 7.31 (m, 1H), 7.19 (s, 1H), 7.1 (d, 1H), 6.88 (d,1H), 4.86 (m, 1H), 4.58 (s, 1H), 4.32 (d, 1H), 4.25 (m, 2H), 3.94 (m,2H), 3.8 (m, 1H), 3.35 (s, 3H), 3.2 (m, 1H), 3.0 (m, 1H), 2.36 (s, 3H),1.69 (s, 3H).

Example 418 Preparation of Compound Nos. V-15 and V-15a-d

Ethyl2-(2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethoxy)acetate(170 mg, 0.392 mmol) in 2N LiOH solution (5 mL) was stirred at RT for 3h. The desired product was detected by LCMS. The reaction mixture wasconcentrated and the crude product was purified by reverse phasechromatography to yield2-(2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethoxy)aceticacid (13 mg). ¹H NMR (CD₃OD, freebase) δ (ppm): 8.45 (d, 2H), 7.42 (d,2H), 7.22 (s, 1H), 7.2 (d, 1H), 7.0 (d, 1H), 5.09 (m, 2H), 4.6 (s, 1H),4.45 (dd, 1H), 4.29 (m, 2H), 4.19 (m, 1H), 3.96 (m, 2H), 3.81 (d, 1H),3.7 (t, 1H), 3.2 (d, 1H), 3.1 (m, 1H), 3.82 (m, 1H), 2.4 (s, 3H), 2.34(m, 1H), 2.09 (m, 1H). Separation by chiral HPLC provides diastereomersV-15a-d.

Example 419 Preparation of Compound Nos. V-18 and V-18a-d

2-(10-Methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethanol(350 mg, 1 mmol), succinic acid (118 mg, 1 mmol) anddimethylaminopyridine (122 mg, 1 mmol) in DCM (20 mL) were stirred atRT. Dicyclohexylcarbodiimide (206 mg, 1.6 mmol) in DCM (20 mL) was addeddropwise and the reaction mixture was stirred at RT for 2 h. Thereaction mixture was concentrated to obtain the crude product that waspurified by reverse phase HPLC to yield4-(2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)-1-(pyridin-4-yl)ethoxy)-4-oxobutanoicacid (96 mg). ¹H NMR (CD₃OD, freebase) δ (ppm): 8.46 (d, 2H), 7.33 (d,2H), 7.27 (d, 1H), 7.23 (s, 1H), 7.01 (d, 1H), 6.07 (t, 1H), 4.8 (t,2H), 4.5 (m, 2H), 3.55 (m, 2H), 3.45 (m, 1H), 3.0 (q, 2H), 2.7 (m, 1H),2.54 (m, 2H), 2.39 (s, 3H), 2.37 (m, 1H), 2.1 (m, 4H). Separation bychiral HPLC provided diastereomers V-18a-d.

Example 420 Preparation of Compound Nos. V-21 and V-21a-b

To a solution of the mesylate compound (2 g, 4.46 mmol) in DMF (25 mL)was added sodium azide (435 mg, 6.69 mmol) and reaction mixture wasstirred at 100° C. for 1 h. The progress of reaction was monitored byNMR. The reaction mixture was diluted with water (100 mL) and extractedwith EtOAc (2×150 mL). The organic layer was washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure toyield6-(2-azido-2-(2,4-difluorophenyl)ethyl)-3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(1.6 g). ¹H NMR (CDCl₃, freebase) δ (ppm): 7.4 (q, 1H), 7.2 (s, 1H),7.18 (d, 1H), 7.01 (d, 1H), 6.99 (d, 1H), 6.92 (d, 1H), 5.13 (dd, 1H),4.26 (dd, 1H), 4.2 (dd, 1H), 2.9 (d, 1H), 2.93 (m, 2H), 2.8 (m, 1H),2.83 m (4, H), 2.5 (s, 3H), 2.46 (s, 3H). Separation by chiral HPLCprovides enantiomers V-21a-b.

Example 421 Preparation of Compound Nos. V-22 and V-22a-b

Methanesulfonicacid-1-(6-carbamoyl-pyridin-3-yl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethylester (300 mg, 0.678 mmol) was dissolved in 5 mL DMF, and sodium azide(88 mg, 1.357 mmol) was added, and the mixture heated at 100° C. for 1h. The reaction mixture was monitored by LCMS. After completion ofreaction, the reaction mixture was cooled to RT and diluted with water(15 mL) and extracted with EtOAc (3×30 mL). The combined organic layerwas washed with water (4×40 mL), dried over anhydrous sodium sulfate andconcentrated to obtain the crude product that was purified by reversephase chromatography to yield5-[1-azido-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-pyridine-2-carboxylicacid amide (135 mg). ¹H NMR (CD₃OD, TFA salt) δ (ppm): 8.6 (dd, 1H), 8.1(t, 1H), 7.9 (t, 1H), 7.33 (dd, 1H), 7.26 (s, 1H), 7.06 (t, 1H), 5.3 (t,1H), 4.7 (dd, 1H), 4.42 (dd, 1H), 4.4 (dd, 2H), 4.3 (m, 1H), 3.8 (m,1H), 3.6 (m, 1H), 3.34 (dd, 1H), 3.1 (d, 3H), 2.4 (s, 3H). Separation bychiral HPLC provides enantiomers V-22a-b.

Example 422 Preparation of Compound Nos. V-23 and V-23a-d

A solution of1-(4-fluorophenyl)-2-(10-methyl-2,3,5,6-tetrahydro-1H-indolizino[7,8-b]indol-7(11cH)-yl)ethylmethanesulfonate (400 mg, 0.9 mmol) and sodium azide (88 mg, 1.3 mmol)in dimethylformamide (10 mL) was stirred at RT for 18 h. The reactionmixture was diluted with ice cooled water (100 mL) and extracted withEtOAc (100 mL). The organic layer was washed with water (5×50 mL), driedover anhydrous sodium sulfate and concentrated to obtain the crudeproduct that was purified by reverse phase HPLC to yield7-(2-azido-2-(4-fluorophenyl)ethyl)-10-methyl-2,3,5,6,7,11c-hexahydro-1H-indolizino[7,8-b]indole(25 mg). ¹H NMR (CD₃OD, freebase) δ (ppm): 7.32 (m, 3H), 7.26 (s, 1H),7.13 (m, 2H), 7.09 (d, 1H), 5.09 (t, 1H), 4.8 (m, 1H), 4.32 (m, 2H),3.44 (m, 2H), 3.3 (m, 1H), 3.1 (m, 1H), 3.0 (d, 1H), 2.8 (m, 1H), 2.6(m, 1H), 2.4 (s, 3H), 2.18 (m, 2H), 2.0 (m, 1H). Separation by chiralHPLC provides diastereomers V-23a-d.

Example 423

Compounds II-266 to II-269 and II-271 to II-299 can be synthesized in ananalogous fashion to other compounds described herein and by referenceto the PCT publications listed in the General Methods above.

Example B1 Determination of the Ability of Compounds of the Invention toBind an Adrenergic Receptor

Adrenergic α_(2B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2B) receptor expressed inChinese hamster ovary (CHO) K1 cells (Uhlen, S. et al, Eur. J.Pharmacol. 343(1):93, 1998) in a modified Tris-HCl buffer (50 mMTris-HCl, pH 7.4, 12.5 mM MgCl2, 1 mM EDTA, 0.2% BSA) was used.Compounds of the invention were incubated with 2.5 nM [3H]Rauwolscinefor 60 min at 25° C. Non-specific binding was estimated in the presenceof 10 μM Prazosin. Receptor proteins were filtered and washed, thefilters were then counted to determine [3H]Rauwolscine specificallybound. Compounds were screened at 1 μM or lower, using 1% DMSO asvehicle. Compounds of the invention were tested in this biochemicalassay and percent inhibition of specific binding was determined.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table B1.

Adrenergic α_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2A) receptor expressed ininsect Sf9 cells (Uhlen, S. et al, J. Pharmacol. Exp. Ther. 271:1558,1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mMMgCl₂, 2 mM EDTA) was used. Compounds of invention were incubated with 1nM [³H]MK-912 for 60 min at 25° C. MK912 is(2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4′(1′H)-pyrimidin]-2′(3′H)-onehydrochloride. Non-specific binding was estimated in the presence of 10μM WB-4101 (2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxanehydrochloride). Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]MK-912 specifically bound. Compoundswere screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds ofthe invention were tested in this biochemical assay and percentinhibition of specific binding was determined. Biochemical assay resultsare presented as the percent inhibition of specific binding in Table B1.

Adrenergic α_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1B) receptor obtained from Wistar Ratliver (Garcia-S'ainz, J. et al, Biochem. Biophys. Res. Commun. 186:760,1992; Michel, A. et al, Br. J. Pharmacol. 98:883, 1989) in a modifiedTris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used.Compounds of the invention were incubated with 0.25 nM [³H]Prazosin for60 min at 25° C. Non-specific binding was estimated in the presence of10 μM phentolamine. Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]Prazosin specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Compounds of the invention were tested in this biochemical assay andpercent inhibition of specific binding was determined. Biochemical assayresults are presented as the percent inhibition of specific binding inTable B1.

Adrenergic α_(1D)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(1D) receptor expressed inhuman embryonic kidney (HEK-293) cells (Kenny, B. et al, Br. J.Pharmacol. 115(6):981, 1995) in a 50 mM Tris-HCl buffer, pH 7.4, wasused. Compounds were incubated with 0.6 nM [³H]Prazosin for 60 min at25° C. Non-specific binding was estimated in the presence of 10 μMphentolamine. Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]Prazosin specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table B1.

TABLE B1 Percentage inhibition of ligand binding to aminergic Gprotein-coupled receptors by compounds of the invention: CompoundAdrenergic (0.1 μM)* Adrenergic (0.03 μM)* No. α_(1B) α_(1D) α_(2A)α_(2B) α_(1B) α_(1D) α_(2A) α_(2B)  1 32 16 6 74 — — — —  2 27, 28 13 4,19 95 — — — 75  3 51, 54 12 12, 37 100, 103 24 —  4 99  3a 12, 44 — 1662 18 — — 26, 30  3b 50, 55, 18 21, 22, — 27, 32, —  1 100, 101, 57, 6123, 25 34 102, 112  4 51, 60 12 12, 41 101 — — — 106  4a 52, 57 — 19, 24104 25 —  5 99, 103  4b 58 — 7 — — — — 46  5 14, 21  4 13 96 — — — 100 5a 18 — 0 57 — — — 29, 38  5b 23, 30,  1 18, 21, 82, 100, 10, 11, — 4,6, 15 81, 86, 33 22 107 15 90, 100  6 8 — 2 — — — — 62  7 35 — 16 — — —— 59  7a 28 — 1 — — — — 59  7b 37 — 25 — — — — 74  8 58 — 23 — — — — 61 8a 39 — 15 — — — — 22  8b 61, 63 — 8, 12 78 24 — — 49  9 5 — −4 — — — —36  9a 11 — 4 — — — — 23  9b 10 — 10 — — — — 50  10a 30 — 8 — — — — 34 10b 28 — 15 — — — — 91  11a 16 — −6 — — — — 28  11b 18 — 13 — — — — 64 12a 23 — 3 — — — — 24  12b 8 — 3 — — — — 21  13 83 — 18 — — — — 92  13a75 — −2 — — — — 37  13b 91 — −2, 21 — 68 — — 100, 102  14a 43, 44 — 8,26 — 17 — — 97, 98  14b 25 — −6 — — — — 14  15 93 — 19 — — — — 93  15a81 — 6 — — — — 65  15b 89, 93 — 21, 24 — 73 — — 103  16a 47 — 9 — — — —33  16b 16 — 2 — — — — 2  17 18 — 19 — — — — 37  17a 13 — 19 — — — — 32 17b 16 — 9 — — — — 20  18a 55 — 50 — — — — 54  18b 87 — 32 — — — — 61 19a 75 — 21 — — — — 75  19b 62 — 9 — — — — 27  20a 67 — 29 — — — — 28 20b 94 — 28 — — — — 36  21a 5 — −1 — — — — −2  21b −2 — −3 — — — — 1 22a 19 — 16 — — — — 22  22b 9 — 0 — — — — 30  23a −20 — 4 — — — — 6 23b 4 — 1 — — — — −3  24a 8 — 8 — — — — 63  24b 8 — 15 — — — — 29  25a4 — 15 — — — — 54  25b 12 — 18 — — — — 75  26a 52, 61 — 23, 33 — 32 — 14101, 107  26b 15 — 12 100 — — — 75, 88  26c 1 — 19 — — — — 1, 7  26d −2— 0 — — — — 6, 11  27a 59, 64 — 2, 11 94 34 — — 76, 83  27b 6, 16 — 0,18 48 — — — 30, 36  28a 41 — 28 — — — — 96  28b 20 — 24 — — — — 37  2924  1 10 100 — — — —  29a 32, 38 — 35, 39 — 19 — 16 98, 100  29b 14 — 10— — — — 46  30 86 49 63 91 — — — —  30a 57 — 19 — — — — 79  30b 89, 91 —74, 75 — 68 — 42 100, 102  31a 25, 28 — 19, 27 — 16 — 11 93, 97  31b 3 —14 — — — — 36  32 12  7 28 86 — — — —  33a −2 23 26 −3 — — — —  33b 0 14−7 2 — — — —  34 30  2 28 38 — — — —  34a 11 19 29 20 — — — —  34b −2 133 1 — — — —  35a 9  6 20 62 — — — —  35b 5 −13  12 47 — — — —  36a 14 —8 — — — — 33  36b 11 — 0 — — — — −1  37a −5 — 18 — — — — 2  37b −10 —−20 — — — — −3  37c 2 — 6 — — — — 0  37d 2 — 8 — — — — −3  38 20 — −1 —— — — 56  38a 11 — 14 — — — — 35  38b 20 — −1 — — — — 17  39 25 — 1 — —— — 89  39a 38, 33 — 13, 15 92  9 —  5 86  39b 24 — 1 — — — — 28  40a 2— 7 — — — — 27  40b −2 — 13 — — — — 29  41 57 — 24 — — — — 45  41a 43 —−9 — — — — 14  41b 50 — 8 — — — — 50  42a 15 — 3 — — — — 29  42b 19 — 12— — — — 34  43 21 — −1 — — — — 24  43a 33 — 9 — — — — 51  43b 46 — 13 —— — — 27  44 −3 — −1 — — — — 56  44a 12 — 11 — — — — 33  44b 18 — 1 — —— — 75  45a 23 — −4 — — — — 54  45b 24 — 16 — — — — 96  47a 58 — 10 — —— — 40  47b 70 — 41 — — — — 119  47c 6 — 4 — — — — 53  47d 5 — −3 — — —— 30  48a 16 — 12 — — — — 58  48b 14 — 17 — — — — 86  49a 4 — 1 — — — —18  49b 5 — 6 — — — — 19  51 43 — 20 — — — — 82  51a 8 — 11 — — — — 21 51b 36 — 26 — — — — 90  52a 9 — 5 — — — — 21  52b 73 — 29 — — — — 93 53a 12 — 10 — — — — 37  53b 14 — 12 — — — — 85  54a 39 — 30 — — — — 105 54b 71 — 66 — — — — 106  55 37 — 13 — — — — 63  55a 28 — 11 — — — — 14 55b 57 — 7 — — — — 67  56a 1 — 11 — — — — 20  56b 6 — 17 — — — — 28 57a 3 — 22 — — — — 16  57b 9 — 24 — — — — 84  58 21 — −1 — — — — 26 58a 7 — 9 — — — — 5  58b 24 — 0 — — — — 39  59a 11 — 18 — — — — 15  59b7 — 12 — — — — 31  60 65 35 26 93 — — — 66  61 60 37 30 85, 94 28 14 —65, 80  62 16 — 1 — — — — 76  63a 10 — 16 — — — — 83  63b −5 — 3 — — — —41  64 25 — 12 — — — — 62  65 −13 — −3 — — — — 64  66 48 — 15 — — — — 69 67 12 — −7 — — — — 17  68 2 — 1 — — — — 4  69a 4 — 11 — — — — 10  69b 8— 7 — — — — 19  70 8 — 10 — — — — 26  71 11 — 11 — — — — 9  72 6 — −2 —— — — 12  73 17 — 15 — — — — 61  74 81 57 6 104 — — — —  74a 91, 96 6122, 27 101 81 42 — 93  74b 28 — 14 — — — — 27  75a 61 — 11 — — — — 77 75b 16 — 5 — — — — 43  75c 59 — −2 — — — — 11  75d 26 — 49 — — — — 102 76a 78 — 21 — — — — 92  76b 71 — 18 — — — — 34  76c 33 — 5 — — — — 35 76d 51 — 40 — — — — 91  77 5, 6 10 −1, 22 91 — — — 84  78 11, 12 22 −7,18 87 — — — 67  79 34 — 19 — — — — 77  80 49 — 12 — — — — 81  81 25 — 26— — — — 96  82 16 — 5 — — — — 79  83 9, 15 13 21, 29 78 — — — 63  84 6936 27 84 — — — —  85 26 17 12 60 −3 — — 40  86 62 62 27 77 — — — —  87 524 14 66 — — — —  88 10 36 2 90 — — — —  89 79 68 23 57, 79 — — — 25  9057 20 22 91 — — — —  90a 74 — 71 — — — — 97  90b 81 — 82 — — — — 97  9152, 53, 25, 30, 5 82, 83, 25, 28, 7, 11,  6 53, 56 58 32 87 32 21  92 7746 30 77 — — — —  93 25  6 21 87 — — — —  93a 37 — 25, 36 — 13 — 14 63,102  93b 1 — −5 — — — — 26  94 40 10 11 66 — — — —  95 52 29 9 105 — — ——  96 25  3 29 71 — — — —  97 3 −7 −12 88 — — — —  98 81, 83 31, 35 26,32 96, 103 — — — —  99 69 34 29 85 — — — — 100 73 47 20 72 — — — — 10161, 79 45, 48 14, 15 63, 76 — — — — 102 40 21 21 77 — — — — 103 49 20 1980 — — — — 105 57 36 14 68 — — — — 106 65 45 6 79 — — — — 107 56 63 1085 — — — — 108 42 21 20 88 — — — — 109 13 21 25 69 — — — — 110 5 35 2762 — — — — 111 56 77 0 65 — — — — 112 44 40 26 79 — — — — 113 12  3 2987 — — — — 114 15 15 21 58, 71 — — — 42 115 19 24 21 94 — — — — 116 2326 22 75 — — — — 117 59 — 18 68 — — — — 118 35  7 19 60 — — — — 119 14−6 14 60 — — — — 120 21, 22 14, 26 45, 48 55, 70  4  3 25 39 121 6 44 1688 — — — — 122 51 84 13 96 — — — — 124 19 12 −2 63 — — — — 125 −3  1 −468 — — — — 126 30 46 12 82 — — — — 127a 26 — 9 74 — — — 43 127b 13 — 4 —— — — 1 128a 37, 45 — 31, 34 104 14  9 97, 100 128b 45 — 22 — — — — 54129a 73 — 46 — — — — 86 129b 69 — 55 — — — — 89 129c 94, 96 — 29, 35 —86 — 14 100 129d 94, 99 — 90, 96 — 93 — 87 97, 104 130a 66, 68 — 82, 89107 32 — 56 100, 104 130b 8, 11 — 31, 44 93  2 — 13 89, 92 131a 24 — 10— — — — 30 131b 36 — 11 90 — — — 53, 63 132 28 — 19 — — — — 91 133a 57 —13 — — — — 52 133b 40, 42 — 34, 39 94 16 27 87, 88 134a 27 — 4 — — — —42 134b 93, 95 — 23, 29 — 78 — — 102, 103 135a 60 — 4 — — — — 42 135b 30— 22 — — — — 68 136a 54 — 16 — — — — 34 136b 90 — 21 — — — — 69 137a 94— 19 — — — — 104 137b 23 — 6 — — — — 30 138a 61 — −8 — — — — 63 138b 22— 4 — — — — 25 139 72 — −2 87 46 — — 59, 83 139a 17 — 16 — — — — 88, 101139b 11 — 6 — — — — 59 140 37 — −2 — — — — 49 140a 59 — 11 — — — — 76140b 18 — 3 52 141 23 — 5 — — — — 76 141a 25 — −5 — 70 141b 28 — 19 —79, 86 142a 68 — 19 95 — — — 71 142b 83 — 63 — — — — 99 143a 43 — 19 — —— — 77 143b 17 — 0 — — — — 49 144a 57 — 1 — — — — 40 144b 53, 60, 66 —3, 4 100, 102 28, 36 — — 83, 85, 87 145 49 — 6 — — — — 61 146a 41 — −1 —— — — 37 146b 11 — 21 — — — — 63 147 7 — 19 — — — — 91, 102 147a 33 — 3— — — — 72 147b 82 — 36 — — — — 93 148a 23 — −5 — — — — 52 148b 71, 74 —37 106 35 — — 105 148c 6 — −1 — — — — 16 148d 19 — −11 — — — — 11 149a12 — −4 — — — — 16 149b 16 — 19 — — — — 32 150a 16 — 16 100 — — — 88, 96150b 7 — 5 — — — — 9 151a 11 — 15 — — — — 93 151b 9 — 8 — — — — 37 152a20 — 17 — — — — 20 152b 7 — 10 — — — — 19 153 17 — 6 — — — — 17 154 86 —15 — — — — 58 154a 39 — 4 — — — — 31 154b 95 — 5 95 80 — — 80, 83 155 15— 14 — — — — 36 155a 9 — −1 — — — — 10 155b 1 — 5 — — — — 5 156 21 — 1 —— — — 6 157 57 — 6 — — — — 43 158 8 — −1 — — — — 43 159a −2 — 10 — — — —37 159b 53 — −12 — — — — 52 160a 35 — −12 — — — — 43 160b 65 — 5 — — — —41 168 23 — 16 — — — — 32 169 2 — 15 — — — — 20 172a 54 — 18 — — — — 65172b 92 — 46 — — — — 93 173a 5 — 15 82 — — — 61, 68 173b 8 — −2 — — — —28 174a 13 — 22 86 — — — 62, 71 174b 11 — 6 — — — — 15 175a 11 — 11 90 —— — 69, 73 175b 4 — 7 — — — — 4 176a 79 — 32 105 52 — — 93, 98, 100 176b41 — 12 — — — — 67 179 6 — 6 — — — — 8 180 87 74 95 99 70 — — 91 181 3032 89 92 −4 — — 70 182 29 16 69 91 13 — — 83 183 71 36 93 80 50 — — 68183a 77 — 56 — — — — 82 183b 93 — 93, 97 — — — 84 98 184 — — 93 — 60 24— 95 185 86 58 62 94, 97 63 47 37 73, 77 186 53, 55 51, 55 54, 72 100,101 24 31 53 94, 97 187 71 83 63, 84 84, 98 — — 41 78 188 60 48 66, 90105 — — 35 — 189 31, 55 16 81, 86 104, 107 26 — 71 96 190 14, 15 31 70,89 84, 99  9 — 49 88 191 10, 20 43 89, 98 89, 99  2 — 85 84 193 93 88 77103 — — — — 193a 89 — 85 — — — — 98 193b 91 — 83 — — — — 104 194a 100 —98 — — — — 106 194b 100 — 94 — — — — 103 196a 54.6 — 58, 71 — 30 — 3793, 103 196b 37 — 19 — — — — −2 197a 82 — 31 — — — — 81 197b 96 — 56, 77— 89 — 50 101, 105 198a 24 — 10 — — — — 47 198b 84 — 44 — — — — 103 199a82 — 96 — — — — 94 199b 88 — 61 — — — — 27 200 83 69 92 — 63 — 81 — 20150 18 67 36 22 — — 16 202 52 52 92 22 29 — — 7 203 71 47 88 41 37 — — 23203a 76 — 71 — — — — 36 203b 47 — 31 — — — — 24 204 — — 87 107 — — — —205 — — 69 70 — — — — 206 — — 86 102 46 42 — — 207 — — 90 106 49 39 — —208 — — 101 97 60 41 — — 209 — — 80 84 — — — — 210 — — 88 63 — — — — 211— — 88 108 63 44 — — 212 — — 66 64 — — — — 213 — — 98 68, 97 53 53 — 26214 18 — 58, 64 80 — — 37 48 215 — — 97 102 — — — — 216 65 — 76, 98 103,106 34, 47 38 58 98 217 62 — 74 102 — — — — 218 — — — — 79 60 85 110 219— — — — —  3 69 — 221 65 16 56 80 — — — — 222 95 101  96 104 — — — — 22321 — 69 — — — — 47 224 70 26 52 69 — — — — 225 27 12 75 80 — — — — 22688 48 85 83 — — — — 227 21 −2 66 98 — — — — 228 64 19 77 42 — — — — 22917  8 53 90 — — — — 230 94 58 87 93 — — — — 231 48 26 65 87 — — — — 23287 43 87 102 — — — — 233 73 28 80 103 — — — — 235 48 11 80 96 — — — —236 94 85 99 98 — — — — 237 80 52 98 99 — — — — 238 67 25 94 98 — — — —239 19 −11  52 30 — — — — 240 74, 75 44, 47 82, 87 83, 97 — — — — 24181, 82 47, 49 75, 78 91, 93 — — — — 242 53 37 50 98 — — — — 243 58 4590, 98 105 — — 73 — 244 78 42 76 99 — — — — 245 69 35 65 96 — — — — 24682 68 86 101 — — — — 247 95 81 96 89 — — — — 248 76 31 90 95 — — — — 24995 82 98 98 — — — — 250 37 22 62 105 — — — — 251 89 53 85 101 — — — —252 36 13 66 52 — — — — 253 54, 55 18, 24 44, 64 64, 86 — — — — 254a 7536 58 85 — — — — 254b 63 22 57 79 — — — — 255 55 43 63 96 — — — — 256 4723 55 58 — — — — 257 51 24 84 100 — — — — 258 93 74 94 99 — — — — 259 7153 82 98 — — — — 260 45 26 54 92 — — — — 261 50 30 84 84 — — — — 262 5235 87 74 — — — — 263 1  6 61 54 — — — — 264 79 46 81 82 — — — — 265 5030 67 70 — — — — 266 63 72 62 92 — — — — 267 7 26 63 85 — — — — 268 5739 90 94 — — — — 269 36 44 61 83 — — — — 270 50 66 96 76 — — — — 271 6583 97 71 — — — — 272a 27 12 33 −10 — — — — 272b 30 36 68 72 — — — — 27388 71 67 89 — — — — 274 28 25 68 27 — — — — 275 75 61 51 94 — — — — 27686 81 71 101 — — — — 277 71 84 98 97 — — — — 278 62 44 93 98 — — — — 27979 93 90 92 — — — — 280 76 65 97 98 — — — — 281 67 47 72 90 — — — — 28233 30 75 101 — — — — 283 63 46 90 89 — — — — 284 83 81 97 76 — — — — 28563 71 98 97 — — — — 286 26 19 80 60 — — — — 287 81 69 99 98 — — — — 288a89 88 98 104 — — — — 288b 39 17 67 84 — — — — 289a 51 57 60 90 — — — —289b 12 −2 53 54 — — — — 290 90 79 80 96 — — — — 291 88 85 102 105 — — —— 292 13 23 58 104 — — — — 293 73 82 96 93 — — — — 294 76 39 94 41 — — —— 295 15  7 69 79 — — — — 296 20 33 60 70 — — — — 297 69 36 50 46 — — —— 298 60 17 54 51 — — — — 299 78 47 52 54 — — — — 300 14 29 67 86 — — —— 301 29 36 87 84 — — — — 302 23 17 81 35 — — — — 303 16 51 62 71 — — —— 304 15 27 79 81 — — — — 305 20 41 93 79 — — — — 306 18 12 78 14 — — —— 307 93 81 93 98 — — — — 308 79 56 86 97 — — — — 309 23 40 57 37 — — —— 310 63 47 69 87 — — — — 311 87 79 91 97 — — — — 312 71 50 56 93 — — —— 313 92 53 73 73 — — — — 314 92 71 91 50 — — — — 315 4  3 59 48 — — — —316 93 81 90 45 — — — — 317 89 71 61 7 — — — — 318 94 60 95 103 — — — —319 13  8 63 4 — — — — 320 61 56 66 18 — — — — 321 94 66 59 90 — — — —322 59 22 58 49 — — — — 323 85 69 92 95 — — — — 324 63 31 67 99 — — — —325 −1  1 81, 84 −6 — — 53 — 326 33 35 51 93 — — — — 327 −5  4 58 −4 — —— — 328 95 80 76 93 — — — — 329 68 78 60 104 — — — — 330 98 72 58 99 — —— — 331 53 70 53 99 — — — — 332 41 51 94 86 — — — — 333 65 16 52 88 — —— — 334 91 72 55 82 — — — — 335 82 73 60 99 — — — — 336 98 — 66 — — — —104 338 16 — 60 — — — — 102 339a 13 — 37 — — — — 86 339b 10 — 64 — — — —87 II-1a 6 — 15 — — — — 14 II-1b −7 — 1 — — — — 32 II-2 74 — 49 — — — —96 II-4a 72 — 35 — — — — 79 II-4b 98 — 57 — — — — 100 II-5 2 — 9 — — — —4 II-6a 66 — 45 — — — — 85 II-6b 91 — 81 — — — — 102 II-7 95 — 52 — — —— 100 II-8 6 — 9 — — — — 70 II-9 30 — 7 — — — — 78 II-10 7 — 10 — — — —47 II-11 63 — 25 — — — — 70 II-11a 9 — 22 — — — — 53 II-11b 76 — 43 — —— — 89 II-12 18 — 11 — — — — 65 II-12a 26 — 25 — — — — 89 II-12b 11 — 15— — — — 65 II-13 9 — 9 — — — — 73 II-14a 30 — 34 — — — — 88 II-14b 8 —17 — — — — 33 II-15a 61 — 7 — — — — 47 II-15b 5 — 18 — — — — 40 II-16a20 — 11 — — — — 39 II-16b 32, 46 — 32 88 16 — — 65, 73 II-17 8 — 4 — — —— 7 II-18 −7 −9 14 −15 — — — II-19 8 — 8 — — — — 21 II-39 16 13 27 −14 —— — — II-40 — — 36 — — — — II-48 27  8 26 0 — — — — II-49a 47 — 34 — — —— 43 II-49b 69 — 18 — — — — 50 II-56 54 11 31 78 — — — — II-57a 20 — 22— — — — 38 II-57b 31 — 31 — — — — 45 II-58 16 — 16 — — — — 58 II-60 11 —9 — — — — 54 II-61 — — — 47 — — — — II-62 14 — 5 — — — — 37 II-63 55 —39 — — — — 90 II-64 23 — −3 — — — — 54 II-65 10 — 12 — — — — 25 II-66 27— 0 — — — — 46 II-67 7 — −11 — — — — 43 II-68 12 — 5 — — — — 17 II-69 45— 11 — — — — 14 II-70 — — — 34 — — — — II-71 3 — −3 — — — — 11 II-72 30— 25 — — — — 47 II-73 34 — 28 — — — — 33 II-74 11 — 10 — — — — 18 II-758 — 15 — — — — 35 II-76 — — — 103 — — — — II-77 54 66 43 108 — — — —II-78 −11 — 1 — — — — −9 II-79 7 — 0 — — — — 59 II-80 4 — 3 — — — — 9II-81 −1 — 15 — — — — −9 II-82 13 23 45 48, 53 — — — 35 II-83 12 — 2 — —— — 24 II-84 2 — 11 — — — — −11 II-85 −7 — 15 — — — — −2 II-86 44 — 27 —— — — 35 II-87 11 — 1 — — — — 24 II-88 68 — −2 — — — — 48 II-89 13 — −5— — — — 35 II-90 62 — 19 — — — — 55 II-91 16 — −2 — — — — 25 II-92 13 —0 — — — — 25 II-93a 6 — 7 — — — — 24 II-93b 18 — 4 — — — — 56 II-94a 10— 0 — — — — 8 II-94b 7 — −5 — — — — 24 II-95a 32 — 16 — — — — 53 II-95b−1 — −1 — — — — 12 II-96 39 31 49 95 — — — — II-97 −4 — 4 — — — — 24II-98a 33 — 12 — — — — 10 II-98b 10 — 19 — — — — 5 II-99a 12 — 24 — — —— 49 II-99b 5 — 16 — — — — 7 II-100a 10 — 7 — — — — 12 II-100b 24 — 4 —— — — 1 II-102 2 — 10 — — — — 49 II-103 1  8 −5 35 — — — — II-104 3 — 10— — — — 21 II-105 5 — 7, 18 27 — — — 5, 30 II-106a 25 — 18 — — — — 20II-106b 31 — 8 — — — — 36 II-108a 13 — −2 — — — — 27 II-108b −2 — −6 — —— — 11 II-109a 27 — 2 — — — — 41 II-109b 5 — −10 — — — — 2 II-110 25, 3617 1, 2 47 — — — 11 II-111 42 — 3 — — — — 35 II-112a 5 — 10 — — — — 36II-112b 10 — 3 — — — — 31 II-113a 9 — −3 — — — — 39 II-113b 5 — 19 — — —— 38 II-114a 45 — 12 — — — — 40 II-114b 7 — −5 — — — — 40 II-116 4 — 3 —— — — 43 II-118a 18 — 3 — — — — 27 II-118b 11 — 5 — — — — −3 II-119 2353 −4 27 — — — — II-120a 99 — 65 — — — — 101 II-120b 100 — 98 — — — — 98II-121a 97, 98 — 91, 92 — 90 — 65 103, 104 II-121b 93, 96 — 80, 85 — 77— 54 100, 103 II-122 −2 — −10 — — — — 47 II-123a 41 — 16 — — — — 62II-123b 61 — 75 — — — — 93 II-124a −2 — 23 — — — — 26 II-124b 10 — 7 — —— — 18 II-125a 92 — 62 — — — — 100 II-125b 97, 102 — 97, 98 — 89 — 89103, 106 II-125c 42 — 9 — — — — 67 II-125d 64 — 71 — — — — 88 II-126 −4— 4 — — — — 4 II-127a 83 — 79 — — — — 105 II-127b 65 — 54 — — — — 104II-128a 61 — 34 — — — — 97 II-128b 84, 86 — 74, 77 — 56 50 102, 106II-129 2 — 12 — — — — 1 II-130 43 — 41 — — — — 97 II-130a 92 — 86 — — —— 103 II-130b 3 — 15 — — — — 33 II-131 90 — 85 — — — — 103 II-132a 33 —8 — — — — 40 II-132b 68 — 22 — — — — 70 II-133 — — — −5 — — — — II-134a86 — 19 — — — — 89 II-134b 65 — 6 — — — — 79 II-135a 48 — −3 — — — — 34II-135b 60, 70 — 40 105 26 — — 103, 105 II-136a 60 — 7 — — — — 36II-136b 31 — 5 — — — — 32 II-138 57 — 9 — — — — 77 II-139 34 — 7 — — — —72 II-140 53 — 3 — — — — 72 II-141 7 — −2 — — — — 22 II-142 5 — −4 — — —— 23 II-143 13 — −3 — — — — 22 II-146a 23 — 47 — — — — 102 II-146b 13 —5 — — — — 43 II-146c 17 — 8 — — — — 42 II-146d 13 — 3 — — — — 16 II-147a32 — 57 — — — — 102 II-147b 20 — 15 — — — — 66 II-147c 7 — 3 — — — — 38II-147d 10 — 4 — — — — 13 II-148 21 — 27 — — — — 93 II-149a 90 — 53 — —— — 104 II-149b 59 — 27 — — — — 96 II-149c 49 — 5 — — — — 41 II-149d 41— 7 — — — — 44 II-150 14 — 5 — — — — 30 II-151a 11 — 1 — — — — 27II-151b 13 — 11 — — — — 78 II-152a 19 — 9 — — — — 93 II-152b 2 — 6 — — —— 61 II-152c 6 — 1 — — — — 14 II-152d 5 — 8 — — — — 9 II-153 2 — 2 — — —— 7 II-154 2 — 11 — — — — 73 II-160 7, 14 15 17, 37 35 — — — 39 II-161 7 2 7 13 — — — — II-163 66 28 41 86 — — — — II-164 12  0 15 40 — — — —II-171 95 55 96 94 — — — — II-187 54 — 10 — — — — 27 II-212 29 — 19 — —— — 73 II-213 −3 — 12 — — — — 11 II-215 — — — −5 — — — — II-221 −1 — 10— — — — 0 II-222 19 — 26 — — — — 99 II-223 9 — 8 — — — — 88 II-224 13 —22 — — — — 68 II-225 9 — −1 — — — — 8 II-226 15 — 4 — — — — 40 II-227a25 — 15 — — — — 86 II-227b 8 — 6 — — — — 18 II-227c 20 — 24 — — — — 94II-227d 12 — 6 — — — — 26 II-228 −2 — 3 — — — — 10 II-229 3 — 6 — — — —12 II-230 −2 — 1 — — — — 22 II-231 11 — 9 — — — — −2 II-232 3 — 3 — — —— 28 II-234 −8 −1 7 33 — — — — II-235 58 28 3 45 — — — — II-236 — — — −4— — — — II-238 — — — 98 — — — — II-239 — — — 17 — — — — II-240 57 — 7 —— — — 53 II-241 5 — −1 — — — — −1 II-242 4 — 2 — — — — 3 II-243 91, 93 —19 82 79 — — 58, 61 II-244a 95 — 22 — — — — 102 II-244b 12 — 2 — — — —16 II-245 27 — 7 — — — — 44 II-246 −2 — 47 — — — — 5 II-247 3 — 83 — — —— 19 II-248 4 — 88 — — — — 5 II-249 6 — 74 — — — — 4 II-250 −5 — 57 — —— — 6 II-251 −7 — 81 — — — — −4 II-252 −1 — 91 — — — — 1 II-253 9 — 54 —— — — 16 II-261 71 — 70 — — — — 103 II-262 3 — 10 — — — — 11 II-263 2 —10 — — — — 10 IV-2 — — — 50 — — — — IV-4 2 15 −3 56 — — — — IV-8a 49 — 7— — — — 4 IV-8b 5 — 22 — — — — 3 IV-93a 7 — 18 — — — — 52 IV-93b 65 — −1— — — — 44 IV-209a 89 — 6 — — — — 72 IV-209b 11 — 10 — — — — 13 IV-209c98 — 59 — — — — 102 IV-209d 54 — 8 — — — — 79 IV-210a 70, 75 — 37 — 43 —— 101, 103 IV-210b 10 — 8 — — — — 29 IV-210c −4 — 1 — — — — 10 IV-210d19 — 13 — — — — 87 V-1 15 — 35 — — — — 102 V-1a 20 — 36 — — — — 88 V-1b57 — 29 — — — — 102 V-2 49 — 2 — — — — 61 V-3 22 — 40 — — — — 71 V-14a 0— 18 — — — — 7 V-14b 2 — 3 — — — — 0 V-15 4 — 7 — — — — 20 V-18a 78 — 13— — — — 57 V-18b 95 — 57 — — — — 98 V-21a 68 — 62 — — — — 98 V-21b 34 —43 — — — — 93 V-22 28 — 18 — — — — 90 V-23 94 — 109 — — — — 105 *Whereshown, some compounds were tested in repeat assays, each datapoint isshown.

TABLE B2 Ki values of compounds of the invention*: Compound α_(1D) No.α_(2B) (nM) α_(2A) (nM) α_(1B) (nM) (nM)  3 0.64 0.26 — —  3a 27.41 — ——  3b 0.26, 0.28, 0.46 139, 166, 222 51 258  4a 0.64 176 — —  5a 35 — ——  5b 0.95, 1.06, 4.53 152, 192, 195 184 —  8b 11.65 2104 — —  13b 0.62199 — —  14a 1.92 123 — —  15b 0.64 112 — —  26a 0.56 113 — —  26b 3.06— —  27a 4.32 1101 — —  27b 43.43 3713 — —  29a 1.09 77.23 — —  30b 1.1314.25 — —  31a 1.58 167 — —  39a 2.50 1659 — —  74a 1.42 234 4.72 —  605.84 — — —  61 5.89 — — —  89 32 — — —  91 9.84, 10.68, 11.97 — — —  93a1.14 90.50 — — 114 17.38 — — — 120 20.52 65.83 — — 127a 15.14 — — — 128a0.97 98.62 — — 129c 0.77 88.55 — — 129d 0.35 1.87 — — 130a 1.66 6.91 — —130b 2.52 72.60 — — 131b 7.95 — — — 133b 2.42 59.45 — — 134b 0.43 102 —— 139a 2.36 — — — 139 8.12 390 — — 141b 3.44 — — — 144b 1.70, 2.36 — — —148b 0.43 — — — 147 1.49 — — — 150a 1.57 — — — 154b 3.33 — — — 173a 8.77— — — 174a 7.91 — — — 175a 4.42 — — — 176a 0.53 — — — 183b — 2.72 — —184 — 184 — — 185 3.80 20.97 — — 186 0.52 11.04 — — 187 4.43 17.89 — —189 0.86 2.86 — — 190 2.26 12.83 — — 191 3.23 2.10 — — 196a 1.83 16.80 —— 197b 0.78 11.90 — — 200 — 1.63, 3.21 — — 204 — 2.48 — — 206 — 1.12,6.79 — — 207 — 1.16 — — 213 26.30 — — — 214 12.91 22.67 — — 216 0.959.59 — — 243 — 3.86 — — 325 206 9.88 — — II-16b 5.58 — — — II-82 26.76 —— — II-105 152 — — — II-121a — 4.52 — — II-121b 0.22 9.18 — — II-125b0.16 1.21 — — II-128b 0.49 13.07 — — II-135b 0.53 — — — II-243 9.44 — —— IV-210a 0.33 — — — V-1 0.51 — — — *Where shown, some compounds weretested in repeat assays, each datapoint is shown.

Example B2 Functional Activity on Recombinant Adrenergic α_(1B),Adrenergic α_(2A) Adrenergic α_(2B) and Adrenergic α_(1D) ReceptorsUsing Aequorin and GTPγS Functional Assays

To study the functional activity of compounds of the invention on thehuman recombinant adrenergic α_(2B), adrenergic α_(2A), adrenergicα_(1B) or adrenergic α_(1D) with Aequorin functional assays and on thehuman recombinant adrenergic α_(2B) receptor with GTPγS assay, CHO-K1cell lines expressing adrenergic α_(2B), adrenergic α_(2A), adrenergicα_(1B) or adrenergic α_(1D) recombinant receptor, mitochondrialapoaequorin and Gα16 were used for the Aequorin assay. CHO-K1 cell lineexpressing the recombinant α_(2B) receptor was amplified to preparemembranes used for the GTPγS assay.

The following reference agonists were used as both the reference ligandin agonist mode and as the agonist that needs to be inhibited inantagonist mode.

α_(2A) Assay α_(1B) (aeq) α_(1D) (aeq) (aeq) α_(2B) (aeq) α_(2B) (GTPgS)Agonist Cirazoline Cirazoline UK Oxymetazoline Guanfacine ligand 14304

Aequorin Assay Procedure:

Aequorin adrenergic α_(1B) (FAST-008A) (FIG. 5), adrenergic α_(2A)(FAST-006A) (FIG. 3) or adrenergic α_(2B) (FAST-007A) (FIGS. 1, 2, 3, 6)cells were grown 18 h prior to the test in media without antibiotics.They were then detached by gentle flushing with PBS-EDTA (5 mM EDTA),recovered by centrifugation and re-suspended in “assay buffer”(DMEM/HAM's F12 with HEPES+0.1% BSA protease free). Cells were incubatedat RT for at least 4 h with Coelenterazine h (Molecular Probes). Doseresponse curves with reference compounds were performed before testingthe compounds of the invention. The α_(1B) reference agonist andantagonist were cirazoline and qinazoline, respectively. The α_(2A)reference agonist and antagonist were UK14,304 and rauwolscine,respectively. The α_(2B) reference agonist and antagonist wereoxymetazoline and rauwolscine, respectively.

For agonist testing, 50 μL of cell suspension were injected on 50 μL oftest compound or reference agonist plated in a 96-well plate. Theresulting emission of light was recorded using the Hamamatsu FunctionalDrug Screening System 6000 (FDSS 6000). For antagonist testing,following an incubation of 15 min. after the first injection, 100 μL ofreference agonist at a concentration corresponding to its EC₈₀ wasinjected on the 100 μL of the mixture of cell suspension and testcompound. The resulting emission of light was recorded using the sameluminometer as for agonist testing. To standardize the emission ofrecorded light (determination of the “100% signal”) across plates andacross different experiments, some of the wells contained 100 μMdigitonin or a saturating concentration of ATP (20 μM). Plates alsocontained the reference agonist at a concentration equivalent to theEC₈₀ obtained during the test validation.

Agonist activity of test compound was expressed as a percentage of theactivity of the reference agonist at its EC₁₀₀ concentration. Antagonistactivity of test compound was expressed as a percentage of theinhibition of reference agonist activity at its EC₈₀ concentration.

Compounds were tested for agonist & antagonist activity at the humanadrenergic α_(1B) (FAST-008A), adrenergic α_(2A) (FAST-006A) oradrenergic α_(2B) (FAST-007A) at the following nanomolar concentrations,in duplicate: Agonist (nM): 0.3, 1, 3, 10, 30, 100, 300, 1000, 3000,10000; Antagonist (nM): 0.15, 0.5, 1.5, 5, 15, 50, 150, 500, 1500, 5000.

GTPγS Assay Procedure:

The procedure was carried out with the following: assay buffer [20 mMHEPES pH 7.4; 100 mM NaCl, 10 μg/mL saponin, 1 mM MgCl₂]; membranes[Recombinant CHO-K1-adrenergic α_(2B) membrane extracts thawed on iceand diluted in assay buffer to give 10 μg/well and kept on ice]; GDP[diluted in assay buffer to give 3 μM final concentration]; beads[PVT-WGA (Amersham, RPNQ0001), diluted in assay buffer at 0.5 mg/well];GTPγ³⁵S [(PerkinElmer NEG030X), diluted in assay buffer to give 0.1 nMfinal concentration]; ligand [Guanfacine (Tocris, 1030) as referenceagonist and Rauwolscine (Tocris, 891) as reference antagonist, dilutedin assay buffer]. Membranes were mixed with GDP (volume:volume) andincubated for at least 15 min. on ice. In parallel, GTPγ[³⁵S] was mixedwith the beads (volume:volume) just before starting the reaction.

For agonist testing, the following reagents were successively added inthe wells of an Optiplate (Perkin Elmer): 50 μL of test or referenceligand, 20 μL of the membranes:GDP mix, 10 L of assay buffer and 20 μLof the GTPγ[³⁵S]:beads mix. For antagonist testing, the followingreagents were successively added in the wells of an Optiplate (PerkinElmer): 50 μL of test or reference ligand, 20 μL of the membranes:GDPmix, and then after an incubation of 15 min. at RT, 10 μL of referenceligand at historical EC₈₀ concentration and 20 μL of the GTPγ[³⁵S]:beadsmix.

The plates were covered with a top seal, mixed on an orbital shaker for2 min, and then incubated for 1 h at RT. Then the plates werecentrifuged for 10 min. at 2000 rpm, incubated at RT 4 h and counted for1 min/well with a Perkin Elmer TopCount reader.

Compounds were tested for antagonist activity at the human adrenergicα_(2B) receptor (FAST-007G) (FIG. 4) at the following nanomolarconcentrations, in duplicate: Agonist and antagonist (nM): 0.3, 1, 3,10, 30, 100, 300, 1000, 3000, 10000.

Inverse Agonist Activity

SPA 35S-GTPgS and Radioligand Binding experiments were conducted withEuroscreen membrane preparations. Compound was tested for inverseagonist activity at the human Adrenergic a2A receptor using GTPg35Sbinding functional assay (FAST-006G) in dose-response and in duplicates.As shown in the FIG. 28, Compound No. 129d showed inverse agonistactivity to adrenergic α_(2A) receptor.

Example B3 Cell Culture and Cell Viability Assay

SH-SY5Y cells cultured in DMEM/F12 media supplemented with 10% FBS areseeded in 96-well microplates at 150,000 cells/cm². After 24 h, cellsare depleted from FBS and kept in culture for 24 h before theexperiment. A stock solution is prepared by dissolving the calciumionophore 4-Br-A23187 (Calbiochem Cat. No 100107) in DMSO at 25 mM.Cells are then treated with 4-Br-A23187 (2 μM), hydrogen peroxide (300μM) or the mitochondrial toxin rotenone (25 μM) in the presence ofvehicle or Compound of the Invention for 24 h. Cell death is determinedby measurements of LDH release according to the Cytotoxicity DetectionKitPlus (Roche, Mannheim, Germany). Cell viability is determined bymeasuring the capacity of cells to metabolize MTS tetrazolium (MTS)according to the Cytotoxicity Detection KitPlus (Roche, Mannheim,Germany) and MTS reduction is assessed by the CellTiter 96® AQueous OneSolution Cell Proliferation assay (Promega Corporation, Madison, Wis.,USA). Compounds are screened at 10 nM, using DMSO as vehicle. Assayresults for the experiments with Br-A23187 are presented as the MTSreduction capacity (cell viability) of untreated cells (control),4-Br-A23187-treated cells (vehicle), and co-incubation of Br-A23187 withCompounds of the Invention treated cells and usingp-trifluoromethoxyphenylhydrazone (FCCP) at 10 μM for 30 min as acontrol. This assay assesses the ability of the test compounds toprotect against cell death that is mediated by mitochondrialdysfunction. In the assay, the calcium ionophore 4-Br-A23187 is used tochallenge the cells, causing calcium levels to rise in mitochondria,which leads to depolarization and cell death. Test compounds areassessed for their ability to prevent cell death in response tochallenge with 4-Br-A23187.

Example B4 Cell Culture and Cell Viability Assay

Cell Culture.

SH-SY5Y cells stably transfected with a doxycyline-inducible wild-typeα-synuclein (α-syn) gene along with control SH-SY5Y cellsover-expressing the β-galactosidase (β-gal) gene (a gift from L.Stefanis, Division of Basic Neurosciences, Biomedical ResearchFoundation of the Academy of Athens, Athens, Greece) are cultured asdescribed by Vekrellis et al. (Vekrellis K, Xilouri M, Emmanouilidou E,Stefanis L. (2009). Inducible over-expression of α-syn in human neuronalcells leads to caspase-dependent non-apoptotic death. J. Neurochem. 109,1348-1362). In accordance with this method, cells are cultured andmaintained in RPMI 1640, 10% fetal bovine serum supplemented with 250μg/mL G418 and 50 μg/mL Hygromycin B. Expression of α-syn is switchedoff in stock cultures with doxycycline (2 μg/mL). For experimentalprocedures, cells are plated at (4-8×10⁴ cells/cm²) and differentiatedin absence of doxycycline and in the presence of 20 μM all-transretinoic acid (RA) (Sigma, St Louis, Mo., USA).

Viability Assay:

Cells are cultured in 96-well plates. After 24 h, cells are treated withRA and Compounds of Invention at 0.1 and 10 nM in the absence ofdoxycyline. Culture medium with RA and drugs is fully replaced after 7days. Cell viability is measured by the release of lactate dehydrogenase(LDH) from necrotic cells into the culture medium and by measuring thecapacity of cells to metabolize MTS tetrazolium (MTS) after 14 days inculture. LDH leakage is assessed according to the Cytotoxicity DetectionKitPlus (Roche, Mannheim, Germany) and MTS reduction is assessed by theCellTiter 96® AQueous One Solution Cell Proliferation assay (PromegaCorporation, Madison, Wis., USA).

Immunoblotting of α-Synuclein and α-Synuclein Aggregates:

Cells stably expressing α-synuclein are cultured in 6-well plates at adensity of 4×10⁴ cells/cm² cells per well. Cells are differentiated andtreated with Compound of the Invention at 10 nM in absence of dox after24 h of plating. Drug treatments are repeated after 7 days in freshlyprepared medium containing RA. After 14 days, cells are washed twicewith cold PBS and lysed in lysis buffer containing 1% Triton X-100, 20mM HEPES, 150 mM NaCl, 10% glycerol, 1 mM EGTA, 1.5 mM MgCl₂, 1 mM PMSFpH 7.4, and 1× protease inhibitor mixture (Roche, Mannheim, Germany).Lysates are homogenized and subjected to four successive freeze-thawcycles to disrupt membranes. Triton soluble fractions and tritoninsoluble pellets are obtained by ultracentrifugation at 100,000×g for30 min at 4° C. The concentration of protein in each fraction isdetermined by BCA assay (Thermo Scientific). Samples from total, solubleand triton insoluble fractions, are boiled in 1× sample buffer (20 mMTris, 1% glycerol, 180 mM β-mercaptoethanol, 0.003% bromophenol blue,and 2% SDS, pH 6.8), loaded on 12% SDS-PAGE gels, and transferred topolyvinylidene difluoride (PVDF) membranes (0.2 μM-pore immobilonBiorad). Membranes are blocked in 1×TBS-Tween (20 mM Tris, pH 7.4, 150mM NaCl, and 0.2% Tween 20) containing 5% milk for 1 h and incubatedovernight at 4° C. with the following primary antibodies in blockingsolution at the indicated dilutions: monoclonal anti-α-synuclein α-syn-1(1:1000; BD Transduction Laboratories). (Perrin, R. J., Payton, J. E.,Barnett, D. H., Wraight, C. L., Woods, W. S., Ye, L., and George, J. M.(2003). Epitope mapping and specificity of the anti-α-synucleinmonoclonal antibody Syn-1 in mouse brain and cultured cell lines.Neurosci. Lett. 349, 133-135), and monoclonal vimentin (1:1000; BDPharMingen). Primary antibodies are detected with secondary anti-mouseantibodies conjugated to HRP (1:5000).

Isolation of RNA and RT-quantitative PCR (RT-qPCR):

SH-SY5Y cells stably over-expressing α-syn are treated with Compound ofthe Invention (10 nM). Total RNA from these cells as well as controlcells not treated with Compound is extracted using the E.Z.N.A RNAextraction Kit (OMEGAbiotek, Norcross, Ga.). 1 μg of RNA is reversetranscribed to cDNA using the M-Mulv reverse transcriptase enzyme(Promega Corporation, Madison, Wis., USA). RT-qPCR of cDNA templates iscarried out using TAQMAN probes for human α-synuclein (Hs00240906_M1)and TAQMAN masterMix (Applied Biosystems) and a Mx3005P real-time PCRsystem (Agilent Technologies Inc., Santa Clara, Calif.). Levels ofalpha-tubulin mRNA are used to normalize the amounts of total RNAbetween samples. Fold changes are calculated as described by (Pfaffl, M.W. (2001). A new mathematical model for relative quantification inreal-time RT-PCR. Nucleic Acids Res 29, e45).

Example B5 Insulin Secretion Ability—In Vitro

Islet Isolation and In-Vitro Insulin Release from Rat Islets:

Rat isolated pancreatic islets were prepared from rat pancreas bycollagenase digestion. After digestion, islets were hand-picked andincubated in a humidified atmosphere with RPMI 1640 tissue culturemedium supplemented with 10% (vol/vol) fetal bovine serum andpenicillin/streptomycin [Carter J D, Dula S B, Corbin K L, Wu R,Nunemaker C S. (2009) “A practical guide to rodent islet isolation andassesment.” Biol. Proced. Online 11(1): 3-31]. In-vitro insulinsecretion was measured in static incubations. Prior to experiments,islets were preincubated for 1 hour at 37° C. in a Krebs-Ringerbicarbonate buffer composed of 120 mM NaCl, 25 mM NaHCO₃, 5 mM KCl, 1 mMMgCl₂, 2.5 mM CaCl₂, 2.8 mM glucose and 0.5% bovine serum albumin. Themedium was gassed with 100% CO₂ for 15 minutes to obtain constant pH.Next, groups of 15 islets were incubated in 1 mL for 60 minutes at 37°C. in Krebs-Ringer buffered solution supplemented with glucose (2.8 mMas low glucose or 20 mM as high glucose), Compound No. 129d, clonidine,yohimbine or norepinephrine as indicated. Immediately after incubation,an aliquot of the medium was removed for analysis of insulin content byELISA (Mercodia). FIGS. 6 and 7 show a dose-proportional increase ininsulin release in the presence of Compound No. 129d, in competitionwith either norepinephrine or clonidine.

Example B6 Insulin Secretion Ability—In Vitro

To demonstrate the insulin secretion ability and/or glucose loweringeffect of an α_(2A) and α_(2B) mixed antagonist (e.g., Compound No.129d), several animal models were used, including clonidine (an α_(2A)agonist) induced, norepinephrine (a natural ligand of α_(2A)) induced,glucose induced, and spontaneous (no agonist) rat (nomal Wistar rats orspontaneously hypertensive rats with obesity (SHR.OB)) models ofhyperglycemia and norepinephrine induced and spontaneous (no agonist)obese mouse (ob/ob) models of hyperglycemia. These models and theirpathophysiology were reported in e.g., Kuhn C. M. et al., Pharmacol.Biochem. Behav. 26:491-495 (1987); Velliquette R. A. and Ernsberger P,J. Pharmacol. Exp. Ther. 306:646-657 (2003); Rosengren A. H., et al.,Science, 327:217-220 (2010); Chen B., et al., Exp. Biol. Med.,236:309-414 (2011); and Saperstein R., et al., Metabolism, 39:445-451(1990). To rule out the possible hypoglycemic effects, normoglycemicrats were used. Male or female 16 week old spontaneously hypertensiveobese rats (SHR.OB), 10 week old male Wistar rats and 10 week old maleob/ob mice were utilized in these studies. Free access to standard labchow and reverse osmosis (RO) water was supplied to all rats. Allaspects of this work, including housing and feeding, experimentation anddisposal of animals were performed in general accordance with the Guidefor the Care and Use of Laboratory Animals (National Academy Press,Washington, D.C., 1996).

Effect of Compound No. 129d on Blood Glucose Levels in Clonidine InducedRat Models of Hyperglycemia:

In separate studies, six hour fasted SHR.OB or Wistar rats wererandomized according to their baseline blood glucose levels and dividedinto several groups with an “n” of 4 for group depending on theexperimental design. All the experimental agents were dissolved insterile saline or appropriate solvents and administered sub-cutaneously(SC), oral (PO) or intra-peritoneal (IP) as indicated. The vehicle groupreceived saline alone via SC route. Test Compound No. 129d at doses of 0(vehicle), 6 mg/kg and 18 mg/kg in SHR.OB rats; and 0 (vehicle), 5 mg/kgand 15 mg/kg to Wistar rats were administered via SC route at −30minutes. Hyperglycemia was induced in both SHR.OB and Wistar rats withclonidine at a dose of 0.05 mg/kg via PO route at 0 min. At all thestudy points, blood glucose levels were measured by one touch glucosemeter (Lifescan, Milpitas, Calif.). The tip of the tail was snipped bysharp scissors and gently squeezed for a drop of blood. The glucosestrip was inserted in the slot of the hand-held glucose meter and a dropof blood was added to the strip. Within 20 seconds, the devicedetermined the blood glucose levels. Blood glucose levels were recordedat −30, 0, 15, 30, 60 and 120 minutes. Results are shown in FIGS. 1 and2.

Effect of Compound No. 129d on Blood Glucose and Serum Insulin Levels inNorepinephrine Induced Rat Models of Hyperglycemia:

All experimental conditions and experimental procedures are identical tothat of clonidine induced rat models of hyperglycemia in SHR.OB andWistar rats except norepinephrine was given in the place of clonidine ata dose of 1 mg/kg via IP route; and Compound No. 129d was tested at asingle dose, 15 or 18 mg/kg via SC route; data on glucose are shown inFIGS. 3 and 4. In further studies, both blood glucose and serum insulinlevels were measured in the same study at 10 or 30 mg/kg SC doses ofCompound No. 129d; The results are shown in FIGS. 9 and 10 in SHR.OBrats (n=8 per/group) and in FIGS. 11 and 12 in Wistar rats (n=6/group).

Effect of Compound No. 129d on Blood Glucose and Serum Insulin Levels inNorepinephrine Induced Ob/Ob Mouse Model Hyperglycemia:

Studies with ob/ob mice, all experimental procedures are identical tothat of norepinephrine induced rat models of hyperglycemia and CompoundNo. 129d was tested via SC route at a dose of 30 mg/kg. Data on bloodglucose in FIG. 13 and serum insulin in FIG. 14 were presented. Numberof mice used per group per time point are 3.

Effect of Compound No. 129d on Blood Glucose and Serum Insulin Levels inOb/Ob Mouse Model Spontaneous Hyperglycemia with No Norephinephrine:

All experimental procedures are identical to that of studies conductedin ob/ob mice where norepinephrine was not given at 0 minutes; andCompound No. 129d at a dose of 30 mg/kg via SC route was dosed at −30minutes. Data on blood glucose in FIG. 15 and serum insulin in FIG. 16were reported. Number of mice used per group and each time point are 3.

Effect of Compound No. 129d on Blood Glucose and Serum Insulin Levels inGlucose Induced (Oral Glucose Tolerance Test—OGTT) Rat SHR.OB Model ofHyperglycemia:

All experimental procedures are identical to that of norepinephrineinduced hyperglycemia in SHR.OB rats except glucose was given in theplace of norepinephrine at 0 minutes at a dose of 6 g/kg via oral routeas reported by Chen et al, Exp. Biol. Med., 236:309-414 (2011); andCompound No. 129d was tested via SC route at doses shown in FIG. 17 forblood glucose; and FIG. 18 for serum insulin. Number of rats used pergroup are 8.

When administered via SC route to SHR.OB or Wistar rats, Compound No.129d markedly reduced blood glucose levels by 30 minutes after theclonidine or norepinephrine challenge and the effect was evidentthroughout the entire study period (FIGS. 1, 2, 3, 4, 9 and 11).Identical effects on blood glucose levels were found in norepinephrineinduced hyperglycemic ob/ob mice (FIG. 13). These effects aredose-dependent and obvious. The glucose lowering effect of Compound No.129d is robust in α_(2A) agonized SHR.OB rats, which is an animal modelof metabolic syndrome, when compared to Wistar rats. In agreement withthe reduction in blood glucose levels, 96d proportionally increasedinsulin secretion in all these models (FIGS. 10, 12 and 14). It alsofound that 129d lowers blood glucose levels even in the absence ofnorepinephrine where ob/ob mice are spontaneously (moderately)hyperglycemic (FIG. 15); and it proportionally enhanced insulinsecretions (FIG. 16). Intriguingly, Compound No. 129d promoted insulinsecretions (FIG. 18) but not reduced blood glucose levels at higher dose(FIG. 17) in a OGTT test conducted in SHR.OB rats, suggesting that itsrole is obvious in insulin secretion but may not improve insulinsensitivity in this particular model.

Effect of Compound No. 129d on Blood Glucose Levels in NormoglycemicRats:

In addition to the studies with rat models of hyperglycemia, the effectof Compound No. 129d at high dose (18 mg/kg, SC) on blood glucose levelswas also tested in normoglycemic SHR.OB rats, which is an animal modelof metabolic syndrome. This is to rule out possible hypoglycemic effectsin normoglycemic rats. The experimental protocol in this study isidentical to that of the other studies except that the rats arenormoglycemic and did not get clonidine or norepinephrine at 0 minutes.Results are shown in FIG. 5, which illustrates that Compound No. 129d asa 18 mg/kg dose did not reduce blood glucose levels or causehypoglycemia in normoglycemic rats.

Compound No. 129d markedly prevented clonidine/norepinephrine inducedhyperglycemia, suggesting the compound can prevent or halt hepaticglucose production via blocking gluconeogenesis or glycogenolysis orboth which is an extra-pancreatic effect.

Compound No. 129d potentiated nateglinide/meglitinides induced insulinrelease in pancreatic beta cell in-vitro model (FIG. 8). This discoverysuggests that it may be used in combination with another anti-diabeticagent such as secretagogues, sensitizers or/and others agents.

Example B7 Blood Pressure Lowering Ability—In Vivo

To demonstrate the blood pressure lowering effect of an α_(2A) andα_(2B) mixed antagonist (e.g., Compound No. 129d), male spontaneouslyhypertensive rats (SHR) were used. SHR rats were anaesthetized withsodium pentobarbital (50 mg/kg IP). The left carotid artery cannulatedwith a polyethylene catheter (38 cm in length; PE60, Portex, Ltd.)connected with a polyurethane tubing (12 cm in length; PU-40, Cat.#BB520-40, Scientific Commodities, Inc.), which was tunneled under theskin and exited through the nape of the neck. The arterial cannula wasconnected to a pressure transducer through a swivel system, allowingfree roaming during continuous recording of mean arterial pressure andheart rate. The animals were housed individually with food and waterfreely available during recovery. On the following day, the arterialcannula was connected via a Statham (P 23×L) pressure transducer to aNEC/San-Ei amplifier and data acquisition and analysis system (Power Lab8/SP) for direct mean arterial pressure and heart rate measurements. Todetermine the effect of Compound No. 129d on systolic blood pressure,oral or i.v. bolus or i.v. escalating doses of compound administrationin every 30 minutes was performed and systolic blood pressure wasmonitored at time points shown in the FIG. 19 (oral), FIG. 20 (i.v.,bolus) and FIG. 21 (i.v., escalating dose). As shown in the FIG. 19,FIG. 20 and FIG. 21, baseline data was collected during 0 to 120 minutestime points; Compound No. 129d was dosed at 120 minutes; and compoundeffect was monitored from 120 minutes to 255 minutes.

When Compound No. 129d was tested oral (10 mg/kg) or i.v., bolus (1mg/kg) or i.v., escalating doses (1, 3, 10 and 30 mg/kg/iv for every 30minutes), its systolic blood pressure lowering effects are robust (FIG.19, FIG. 20 and FIG. 21) which suggests that Compound No. 129d is apromising agent for the management of a pathological condition wheretype-2 diabetes or obesity or metabolic syndrome is clustered withhypertension.

Example B8 Synergistic Studies with Other Secretagogue Drugs

Similar to the methods mentioned in the earlier section (InsulinSecretion Ability—in vitro), male Sprague Dawley rats were anesthetizedwith a mixture of ketamine and xilazine (1:1) and their abdominal wallswere cut open. Ten milliliter Hank's buffer saline containingcollagenase (2 mg/ml) was injected into the common bile duct of the rat.The pancreas swollen with the digestion solution was quickly excised andimmersed into a plastic culture bottle with solution for 12 minutes-14minutes incubation at 37° C. The digested suspension obtained was washedwith Hank's buffer complement with 0.2% bovine serum albumin. Isletswere obtained from a rat by gradient centrifugation (Histopaque-1077).After, islets were cultured for 24 hours in RPMI medium and collectedfor tests. Different scretagogue drugs like sulfonylureas (nateglinide,a meglitinide class) or sulfonylureas (glibenclamide, a secondgeneration sulfonylureas or glimepiride, a third generationsulfonylurea) were tested with Compound No. 129d and found synergism(FIG. 8, FIG. 23 and FIG. 24).

Compound No. 129d Blocks pERK1/2:

For Western blotting, whole-cell extracts, cells were washed withice-cold PBS and lysate with lysis buffer and collected by scraping. Theprotein concentration was determined using a BCA Protein Assay ReagentKit. Cell lysates containing 30 μg proteins were electrophoresed on 10%SDS-PAGE and then transferred onto a PVDF membrane. The membranes wererinsed with TBST, followed by incubation with p-ERK (mouse, 1/1000,SCBT) or ERK (rabbit, 1/1000, SCBT) for 2 or 1 hour, respectively, atroom temperature. After being washed with TBST, the membranes wereincubated with the anti-mouse or anti-rabbit, respectively, HRP antibody(1:5000; Rockland) for 1 hour. Immunoreactive bands were visualized byECL Western blotting detection (PIERCE). As shown in the FIG. 25(Westernblot), Compound No. 129d blocked pERK1/2 norepinephrine mediatedeffects in rat pancreatic islets.

Example B9 Human Clinical Studies

The compound is studied in a clinical trial of adult-onset type 2diabetic patients whose blood glucose levels remain suboptimallycontrolled despite use of metformin. The study compares the activecompound against a matched placebo with the primary objective ofcomparing mean hemoglobin A1c changes from baseline to the end of thestudy between the active compound and placebo.

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

What is claimed is:
 1. A method of treating type 2 diabetes comprisingadministering to an individual in need thereof an effective amount of acompound of the formula (A-III):

or a salt, solvate or N-oxide thereof, wherein: R¹ is H; C₁-C₅ alkyloptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, hydroxyl, carboxyl and perhaloalkyl;C₃-C₈ cycloalkyl optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, hydroxyl,carboxyl and perhaloalkyl; C₂-C₅ alkenyl optionally substituted with 1to 3 substituents independently selected from the group consisting ofhalo, hydroxyl, carboxyl and perhaloalkyl; or —C(O)O—C₁-C₅ alkyl; or istaken together with R^(2a) or R^(3a) to form a propylene (—CH₂CH₂CH₂—)moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together withR^(4a) or R^(5a), where present, to form an ethylene (—CH₂CH₂—) moietyor a propylene (—CH₂CH₂CH₂—) moiety; each n and m is 1, or n is 0 and mis 1, or n is 1 and m is 0; R^(2a) is H; optionally substituted C₁-C₅alkyl; optionally substituted C₂-C₅ alkenyl; or optionally substitutedaryl; or is taken together with R¹ or R^(5a), where present, to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; oris taken together with R^(3a) to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety; or is taken together with R^(4a), wherepresent, to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety; R^(3a) is H; optionally substituted C₁-C₅ alkyl; optionallysubstituted C₂-C₅ alkenyl; or optionally substituted aryl; or is takentogether with R¹ or R^(4a), where present, to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; or is takentogether with R^(2a) to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety; or is taken together with R^(5a), wherepresent, to form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—)moiety; R^(4a) is H; optionally substituted C₁-C₅ alkyl; optionallysubstituted C₂-C₅ alkenyl; or optionally substituted aryl; or is takentogether with R^(3a) to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety; or is taken together with R¹ to forman ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety; or istaken together with R^(2a) to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety; or is taken together with R^(5a), wherepresent, to form a methylene (—CH₂—) moiety; R^(5a) is H; optionallysubstituted C₁-C₅ alkyl; optionally substituted C₂-C₅ alkenyl; oroptionally substituted aryl; or is taken together with R^(2a) to form apropylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety; oris taken together with R¹ to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety; or is taken together with R^(3a) to forma methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety; or is takentogether with R^(4a), where present, to form a methylene (—CH₂—) moiety;each R^(2b), R^(3b), R^(4b) and R^(5b) is independently H, optionallysubstituted C₁-C₅ alkyl, optionally substituted C₂-C₅ alkenyl, oroptionally substituted aryl; X is N or CR^(6a); t is 1, 2 or 3; each R⁶and R^(6a) is independently H; hydroxyl; halo; C₁-C₅ alkyl optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, hydroxyl, carboxyl and perhaloalkyl; C₂-C₅alkenyl; optionally substituted C₁-C₅ alkoxy; or optionally substitutedC(O)C₁-C₅ alkyl; R⁷ is H; halo; optionally substituted C₁-C₅ alkyl; oroptionally substituted aryl; or is taken together with R⁸ and the carbonatom to which they are attached to form a dioxolane ring or a carbonylmoiety; or is taken together with R⁹ to form a C₃-C₅ alkylene when R⁸and R¹⁰ are taken together to form a bond; R⁸ is H; halo; hydroxyl;N(R¹¹)R¹²; SR¹³, S(O)R¹³; SO₂R¹³; —OC(O)N(R¹⁴)R¹⁵; —OC(O)-aryl;—OC(O)-heteroaryl; or —OC(O)C₁-C₅ alkyl optionally substituted withamino; or is taken together with R⁷ and the carbon atom to which theyare attached to form a dioxolane ring or a carbonyl moiety; or is takentogether with R¹⁰ to form a bond; R⁹ is H or optionally substitutedC₁-C₅ alkyl; or is taken together with R⁷ to form a C₃-C₅ alkylene whenR⁸ and R¹⁰ are taken together to form a bond; R¹⁰ is H or optionallysubstituted C₁-C₅ alkyl; or is taken together with R⁸ to form a bond;each R¹¹ and R¹² is independently H or optionally substituted C₁-C₅alkyl; or R¹¹ and R¹² are taken together to form C₃-C₅ alkylene; R¹³ isH or optionally substituted C₁-C₅ alkyl; each R¹⁴ and R¹⁵ isindependently H or optionally substituted C₁-C₅ alkyl; or R¹⁴ and R¹⁵are taken together to form a C₃-C₅ alkylene; and Q is unsubstitutedaryl; unsubstituted heteroaryl; aryl substituted with 1 to 3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino; or heteroaryl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl, halo-substituted C₁-C₅ alkyl,halo-substituted C₃-C₈ cycloalkyl, C₁-C₅ alkoxy, C₃-C₈ cycloalkoxy,cyano, carboxyl, aminoacyl and acylamino.
 2. The method of claim 1,wherein the individual is not responsive to standard treatment of type 2diabetes.
 3. The method of claim 1, further comprising administering tothe individual in need thereof one or more anti-diabetic agents.
 4. Themethod of claim 3, wherein at least one of the anti-diabetic agents isan insulin sensitizer.
 5. The method of claim 1, wherein X is CR^(6a),wherein R^(6a) is H, halo or C₁-C₅ alkyl; and each R⁶ is independentlyH, halo or C₁-C₅ alkyl.
 6. The method of claim 1, wherein X is N.
 7. Themethod of claim 1, wherein R¹ is H or C₁-C₅ alkyl.
 8. The method ofclaim 1, wherein R⁷ is H or C₁-C₅ alkyl, and R⁸ is H, hydroxyl,N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl.
 9. The method of claim 1, wherein R⁷ isH or C₁-C₅ alkyl, and R⁸ is H or hydroxyl.
 10. The method of claim 1,wherein R⁷ is H or C₁-C₅ alkyl, and R⁸ is hydroxyl.
 11. The method ofclaim 1, wherein R⁷ is H, R⁸ is hydroxyl, n is zero and m is
 1. 12. Themethod of claim 1, wherein R⁷ is methyl, R⁸ is hydroxyl, n is zero and mis
 1. 13. The method of claim 1, wherein Q is: unsubstituted pyridyl;unsubstituted pyrimidyl; unsubstituted pyrazinyl; unsubstituted phenyl;unsubstituted imidazolyl; unsubstituted triazolyl; pyridyl substitutedwith 1 to 3 substituents independently selected form the groupconsisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl, carboxyland —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ is independently H oroptionally substituted C₁-C₅ alkyl; pyrimidyl substituted with 1 to 3substituents independently selected form the group consisting of halo,C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷,wherein each R¹⁶ and R¹⁷ is independently H or optionally substitutedC₁-C₅ alkyl; pyrazinyl substituted with 1 to 3 substituentsindependently selected form the group consisting of halo, C₁-C₅ alkyl,halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷, wherein eachR¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅ alkyl;phenyl substituted with 1 to 3 substituents independently selected formthe group consisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl,carboxyl and —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ is independently Hor optionally substituted C₁-C₅ alkyl; imidazolyl substituted with 1 to3 substituents independently selected form the group consisting of halo,C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷,wherein each R¹⁶ and R¹⁷ is independently H or optionally substitutedC₁-C₅ alkyl; or triazolyl substituted with 1 to 3 substituentsindependently selected form the group consisting of halo, C₁-C₅ alkyl,halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷, wherein eachR¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅ alkyl.14. The method of claim 1, wherein: X is CR^(6a), wherein R^(6a) is H,halo or C₁-C₅ alkyl; each R⁶ is independently H, halo or C₁-C₅ alkyl; R⁷is H or C₁-C₅ alkyl; R⁸ is H, hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl;each R⁹ and R¹⁰ is hydrogen; and Q is unsubstituted pyridyl; or pyridylsubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl,carboxyl and —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ is independently Hor optionally substituted C₁-C₅ alkyl.
 15. The method of claim 14,wherein n is 0 and m is 1; R⁷ is H or CH₃; and R⁸ is H or hydroxyl. 16.The method of claim 1, wherein: X is N; R⁷ is H or C₁-C₅ alkyl, R⁸ is H,hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl; each R⁹ and R¹⁰ is hydrogen;and Q is unsubstituted pyridyl; or pyridyl substituted with 1 to 3substituents independently selected from the group consisting of halo,C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl, carboxyl and —C(O)NR¹⁶R¹⁷,wherein each R¹⁶ and R¹⁷ is independently H or optionally substitutedC₁-C₅ alkyl.
 17. The method of claim 16, wherein n is 0 and m is 1; R⁷is H or CH₃; and R⁸ is H or hydroxyl.
 18. The method of claim 1,wherein: n is 0 and m is 1; R¹ is taken together with R^(2a) to form apropylene (—CH₂CH₂CH₂—) moiety; X is CR^(6a), wherein R^(6a) is H, haloor C₁-C₅ alkyl; each R⁶ is independently H, halo or C₁-C₅ alkyl; R⁷ is Hor C₁-C₅ alkyl, R⁸ is H, hydroxyl, N(R¹¹)R¹² or —OC(O)C₁-C₅ alkyl; eachR⁹ and R¹⁰ is hydrogen; and Q is unsubstituted pyridyl; or pyridylsubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, C₁-C₅ alkyl, halo-substituted C₁-C₅ alkyl,carboxyl and —C(O)NR¹⁶R¹⁷, wherein each R¹⁶ and R¹⁷ is independently Hor optionally substituted C₁-C₅ alkyl.
 19. The method of claim 18,wherein R⁷ is H or CH₃; and R⁸ is H or hydroxyl.
 20. The method of claim1, wherein the compound is Compound No. 325, 129d, 130a, II-121b,II-123b, II-127a, II-128b, II-130a, II-131, and II-6b.
 21. The method ofclaim 1, wherein: n is 0 and m is 1; each of R^(2b), R^(3b), R^(4a) andR^(4b) is H; t is
 1. 22. The method of claim 21, wherein X is CH. 23.The method of claim 21, wherein X is N.
 24. The method of claim 21,wherein R¹ is H or CH₃.
 25. The method of claim 21, wherein R^(2a) is Hor is taken together with R¹ to form a propylene (—CH₂CH₂CH₂—) moiety.26. The method of claim 21, wherein each R⁶ and R^(6a) is independentlyH, halo or C₁-C₅ alkyl.
 27. The method of claim 21, wherein R⁷ is H orCH₃.
 28. The method of claim 21, wherein R⁸ is hydroxyl.
 29. The methodof claim 21, wherein Q is: unsubstituted pyridyl; unsubstitutedpyrimidyl; unsubstituted pyrazinyl; unsubstituted phenyl; unsubstitutedimidazolyl; unsubstituted triazolyl; pyridyl substituted with halo, CH₃,CF₃, CONH₂, OH, or OCH₃; pyrimidyl substituted with halo, CH₃, CF₃,CONH₂, OH, or OCH₃; pyrazinyl substituted with halo, CH₃, CF₃, CONH₂,OH, or OCH₃; or phenyl substituted with halo, CH₃, CF₃, CONH₂, OH, orOCH₃.
 30. The method of claim 21, wherein: X is CH; each R⁶ isindependently H, halo or C₁-C₅ alkyl; R⁷ is H or CH₃; R⁸ is hydroxyl;and Q is unsubstituted pyridyl, or pyridyl substituted with H, halo,CH₃, CF₃, or OCH₃.
 31. The method of claim 21, wherein the compound isCompound No. 325, 129d, 130a, II-121b, II-127a, II-128b, II-130a,II-131, and II-6b.
 32. The method of claim 1, wherein the compound bindsto and is an antagonist of the adrenergic receptor α_(2A) and, whereinthe compound either (a) also binds to and is an antagonist of theadrenergic receptor α_(2B) or (b) the compound is not an antagonist ofthe adrenergic receptor α_(2B) and the compound is administered inconjunction with a second agent that reduces blood pressure in theindividual.
 33. The method of claim 32, wherein the compound binds toand is an antagonist of the adrenergic receptor α_(2B).
 34. The methodof claim 32, wherein the compound binds to and is an antagonist of theadrenergic receptor α_(1B).
 35. The method of claim 33, wherein thecompound binds to and is an antagonist of the adrenergic receptorα_(1B).
 36. The method of claim 32, wherein the compound is not anantagonist of the adrenergic receptor α_(2B) and the compound isadministered in conjunction with a diuretic, an angiotensin-convertingenzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist, a betablocker, a calcium channel blocker, or any combination thereof.
 37. Themethod of claim 1, wherein the compound is selected from the groupconsisting of Compound Nos. 6, 9 to 12, 14, 16 to 21, 23 to 28, 39 to40, 42, 44 to 59, 63 to 72, 77 to 82, 104, 108 to 116, 118 to 131, 133to 142, 144 to 171, 173 to 179, 187 to 192, 195 to 198, 220, 269 to 271,273 to 287, 290 to 306, 308 to 319, 321 to 338, 340 to 342, II-1 toII-4, II-6 to II-16, II-18 to II-19, II-39 to II-40, II-58 to II-65,II-67 to II-68, II-70 to II-71, II-75 to II-77, II-80 to II-84, II-88 toII-94, II-96 to II-106, II-108 to II-118, II-120, II-121, II-123 toII-125, II-127 to II-128, II-130 to II-136, II-138 to II-154, II-188 toII-206, II-212 to II-213, II-215, II-220 to II-227, II-229 to II-232,II-240, II-243 to II-253, II-255 to II-269, II-271 to II-272, II-274,II-276 to II-285, II-287 to II-291, II-293 to II-298, IV-I, IV-8 toIV-9, IV-11 to IV-18, IV-49 to IV-58, IV-91, IV-93 to IV-98, IV-129 toIV-138, IV-169 to IV-178, IV-209 to IV-211, IV-213 to IV-218, V-1 toV-23; or a salt thereof.
 38. The method of claim 1, wherein the compoundis selected from the group consisting of:

or a salt thereof.
 39. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 40. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 41. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 42. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 43. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 44. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 45. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 46. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 47. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 48. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 49. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 50. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 51. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 52. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 53. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 54. The method of claim 1, wherein the compound isselected from the group consisting of:

or a salt thereof.
 55. The method of claim 1, wherein the compound isCompound No. 3b, or a salt thereof.
 56. The method of claim 1, whereinthe compound is Compound No. 5b, or a salt thereof.
 57. A method oftreating type 2 diabetes comprising administering to an individual inneed thereof an effective amount of a compound of the formula (H-IC):

or a salt thereof, wherein: X is N; each X¹, X² and U is independently Nor CR⁶; R¹ is H, C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, C₃-C₈ cycloalkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, C₂-C₅ alkenyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, or —C(O)O—C₁-C₅ alkyl; each R⁶ is independently H,hydroxyl, halo, C₁-C₅ alkyl optionally substituted with 1 to 3substituents independently selected from halo, hydroxyl, carboxyl andperhaloalkyl, optionally substituted C₁-C₅ alkoxy or optionallysubstituted —C(O)C₁-C₅ alkyl; R⁷ is H, halo, optionally substitutedC₁-C₅ alkyl, or optionally substituted aryl; Q is aryl or heteroaryloptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, C₁-C₅ alkyl, C₃-C₈ cycloalkyl,halo-substituted C₁-C₅ alkyl, halo-substituted C₃-C₈ cycloalkyl, C₁-C₅alkoxy, C₃-C₈ cycloalkoxy, cyano, carboxyl, —NHC(O)CH₃ and —C(O)NR¹⁶R¹⁷;and each R¹⁶ and R¹⁷ is independently H or optionally substituted C₁-C₅alkyl.
 58. The method of claim 57, wherein Q is optionally substitutedpyridyl.
 59. The method of claim 57, wherein the compound is CompoundNo. 78:

or a salt thereof.
 60. The method of claim 57, wherein the compound isCompound No. 124:

or a salt thereof.
 61. The method of claim 57, wherein the compound isCompound No. 335:

or a salt thereof.